1. Introduction

2. Apoptosis in neurons: an

overview of the mitochondrial

pathway

3. Antiapoptotic drugs

4. Conclusions

5. Expert opinion

Review

An overview of investigationalantiapoptotic drugs withpotential application for thetreatment of neurodegenerativedisordersAntoni Camins†, Francesc Xavier Sureda, Felix Junyent, Ester Verdaguer,Jaume Folch, Carlos Beas-Zarate & Merce Pallas†Institut de Biomedicina (IBUB), Centros de Investigacion Biomedica en Red de Enfermedades

Neurodegenerativas (CIBERNED), Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia,

University of Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain

Importance of the field: The increase in life expectancy in developed coun-

tries has given rise to several emerging social problems. Of particular note

is the dramatic rise in the incidence of neurodegenerative diseases. Given

this new social scenario, there is a need to identify therapeutic strategies

to delay the advance of these pathologies, for which no effective treatment

is currently available.

Areas covered in this review: The present review discusses some of the drugs

that are now under development with antiapoptotic activity or currently on

the market that may have a potential application for the treatment of neu-

rodegenerative diseases. Moreover, we also comment on potential com-

pounds such as resveratrol and melatonin. Despite the lack of information

from clinical trials on these two compounds, they are attracting considerable

attention because of their natural origin and antioxidant and antiapoptotic

action. Furthermore, they do not show toxicity in humans. In addition, we

discuss the potential application of several compounds, such as NMDA

antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of

neurodegenerative disorders.

What the reader will gain: This article will review recent developments in

the field of apoptosis inhibitors, which might provide future tools for the

treatment of the neurodegenerative diseases.

Take home message: The treatment of neurodegenerative diseases is a

major challenge in medicine. This is partly because the incidence of these

disorders is expected to rise in the coming years. New developments in the

field of apoptosis inhibitors may provide future tools for the treatment of

the aforementioned neurodegenerative diseases.

Keywords: Alzheimer’s disease, apoptosis, neuroprotective drugs, Parkinson’s disease

Expert Opin. Investig. Drugs (2010) 19(5):587-604

1. Introduction

The treatment of neurodegenerative diseases is a major challenge in medicine. Thisis partly because the incidence of these disorders is expected to rise in coming years,but also because there is a lack of in-depth knowledge of the precise mechanismsthat lead to a selective loss of a particular population of neurons [1]. This deficiencyclearly hampers the development of new drugs for the management of thesediseases. The scientific community has made a huge effort in recent decades to

10.1517/13543781003781898 © 2010 Informa UK Ltd ISSN 1354-3784 587All rights reserved: reproduction in whole or in part not permitted

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identify the main pathways responsible for neuronal death,only to find that these phenomena are immensely complexand in many cases redundant [2,3]. However, every time aparticular protein is found to be involved in neuronal death,a new opportunity arises to develop novel molecules that exertputative neuroprotective action [3].In addition, the availability of animal models for several

neurodegenerative diseases, such as Alzheimer’s disease andamyotrophic lateral sclerosis (SOD1A) mice, is undoubtedlyaccelerating the discovery of new promising compounds [4,5].Furthermore, these models also allow for the evaluation ofdrugs that have been in use for some time and that appearingto show neuroprotective activity.Alzheimer’s disease (AD) is one of the most devastating

neurodegenerative disorders. At present, it is treated mainlythrough the acetylcholinesterase inhibitors, since the aim ofthe treatment is to increase the acetylcholine levels in thebrain [6,7]. The clinical efficacy of this strategy is low, andthe progression of the disease is not modified. For Parkinson’sdisease (PD), the situation is not much better. This therapeu-tic approach is to increase the levels of dopamine, for thispurpose levodopa-based regime is administered to the PDpatients. Although levodopa is well tolerated and valuable,its efficacy declines as nigrostriatal neurons die [8]. Moreover,it has been suggested that levodopa itself contributes to neuro-nal death as a result of increased oxidative stress in dopami-nergic neurons [8]. In AD, the only drug currently availableto retard the progression of functional decline is memantine,a noncompetitive antagonist that targets NMDA recep-tors [5,7,9]. These receptors have been implicated in neuronaldeath, and blocking these calcium-permeable channels has

proven to be a successful strategy to prevent neuronal deathin vitro and in animal models. Indeed, riluzole, another gluta-mate antagonist, is used to treat patients with amyotrophiclateral sclerosis (ALS) [10]. However, the development ofglutamate receptor antagonists, although intensive, has beendisappointing, and clinical research into drugs like dizocil-pine, selfotel, aptiganel, remacemide and licostinel has beendiscontinued, either because the benefits appear to be limitedor because their side effects are unacceptable [8,9].

Apart from glutamate antagonists, hundreds of compoundsshow neuroprotective properties. These include antioxidantsand immunomodulators, and molecules that act on a numberof targets that have proven highly relevant in apoptoticand necrotic neuronal cell death. However, after decadesof intense research, none have gone beyond clinical trials.Current knowledge of apoptotic pathways has led to thehypothesis that therapeutic action on more than one targetshould offer additional therapeutic benefits [6-9,11-13]. Evi-dence exists in brains of Alzheimer patients of markers orindicators of apoptosis such as neuronal pentraxin 1 (NP1)which is part of the apoptotic neuronal death program [14].Thus NP1 is increased in dystrophic neurites in brains ofpatients with AD. Moreover in AD, abnormal tau depositionis accompanied by an increase in phosphorylated JNK andphosphorylated p38 expression [15].

Therefore, in recent years, several targets have beendefined that merit attention and that may reveal the wayby which new products will reach clinical applications inthe future such as JNK. This article will review recent devel-opments in the field of apoptosis inhibitors, which mightprovide future tools for the treatment of the aforementionedneurodegenerative diseases.

2. Apoptosis in neurons: an overview of themitochondrial pathway

It should be emphasized that the apoptotic process is a phys-iological pathway that is essential for tissue homeostasis. Inphysiological conditions, the apoptotic route serves toremove cells that are no longer required. However, activa-tion of apoptosis in neurons is responsible for the pathogen-esis of neurodegenerative diseases, which usually progressslowly for > 10 years. It is widely accepted that mitochondriaare the main regulators of neuronal apoptosis (Figure 1) [12,13].Thus, before developing effective drugs for neurodegenera-tive diseases, it is crucial to establish how and why neuronsengage in apoptosis [2,3,11-13].

There are two apoptotic pathways: the extrinsic pathway,through the activation of membrane FAS receptors, and theintrinsic or mitochondrial pathway [2,12]. It is believed thatthe induction of apoptosis occurs by a first hit (i.e., a suddenand/or sustained intracellular calcium increase), which indu-ces the activation of signals, such as the production of ROS,which favors DNA damage and endoplasmic reticulum (ER)stress [11]. This damage, in turn, leads to the activation of

Article highlights.

• Neuronal cell death by apoptosis is involved in allneurodegenerative diseases such as Alzheimer’s andParkinson’s diseases.

• Therefore a drug which attenuate or prevents theapoptotic process can be an effective useful tool in thenext years as a therapeutic strategy for the treatment ofneurodegenerative diseases.

• The mitochondrial alteration plays a key role in thisprocess of neuronal death by apoptosis. Therefore, wemust act before mitochondrion is too damaged, sincethis constitutes a point of no return.

• One of the main problems we have today is that theresults obtained in the laboratory are not consistentwith clinical trials. In other words, many moleculesstudied have a good antiapoptotic effect that is notseen in human patients.

• Current clinical trials should have to assess a number ofimportant parameters, such as the length of time thatthe drug should be given, drug dosage, whetherpatients’ neurons return to functioning, and thepossibility of administering more than one drug ascombination therapy.

This box summarizes key points contained in the article.

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the pro-apoptotic Bcl-2 homologues, Bcl-2-associatedprotein X (BAX) and Bcl-2-antagonist killer (BAK), membersof the Bcl-2 family of proteins, which tightly regulate the apo-ptotic process [2-13]. The Bcl-2 family is classified into threesubfamilies. First, there is a subfamily of antiapoptotic pro-teins that includes, among others, Bcl-2, Bcl-xL, Bcl-w andMcl-1. The second subfamily contains a group of pro-apopto-tic proteins, including Bax and Bak. And finally, the third sub-family holds the so-called BH3-only proteins, which includeother pro-apoptotic proteins like Bad, Bid, Bik, Bim, DP5,Noxa and Puma [12,13]. The mitochondrial pathway is a com-plex route, since Bcl-2-regulated apoptosis requires Bax orBak activation to cause mitochondrial damage. Thus, membersof the Bcl-2 family control the integrity of the mitochondrialmembrane in healthy cells and the permeabilization of thismembrane in response to apoptotic stimuli, through oligomer-ization, and the formation of mitochondrial pores in the outermembrane. By this mechanism, specific mitochondrial pro-apoptotic proteins are released to the cytoplasm [3,13]. The firstprotein identified with a pro-apoptotic function was

cytochrome c (Cyt c), a protein that has its own function inthe electron transport chain. Cyt c is released from mitochon-dria to the cytoplasm through the permeability transitionpore (PTP). Many authors suggest that Cyt c release is medi-ated by a prior loss of mitochondrial transmembrane potential;however, others demonstrate that the release of this protein isalso possible without changes in this parameter. Once Cyt c isreleased to the cytoplasm, it triggers the formation of the apop-tosome, a combination of proteins composed by Cyt c, apopto-tic protease activating factor-1 (Apaf-1) and dATP. Theapoptosome triggers pro-caspase 9, and in successive steps thecaspase cascade is amplified by activation of executioner cas-pases, such as caspase 3, 6 and 7 [12]. Therefore, it is importantto emphasize that the last step in apoptosis occurs as a result ofthe activation of these cysteine proteases (caspases), whichdegrade essential intracellular proteins and finally dismantlethe cell [2,3,12,13].

The proteins released by mitochondria are involved in theregulation of downstream components of the cell deathmachinery. The most widely studied and best characterized

Ca2+

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Ca2+

Ca2+

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PermeabilityTransition pore

APAF

Procaspase

9

Apoptosome

Cyt C

AIF

SMAC/Diablo

Caspasecascadeactivation

Apoptosis

BAX

BAK

ROS

Endoplasmicreticulum

Figure 1. Apoptosis can result from the activation of two biochemical cascades, which are known as the extrinsic and the

intrinsic (or mitochondrial) pathways. The intracellular apoptotic (mitochondrial) is triggered by intracellular stimuli such as

Ca2+ overload and over-generation of ROS. Initiator caspase 9 is activated and so can catalyse the proteolytic maturation of

executioner caspases, such as caspase 3, that mediate apoptosis. Mitochondrial membrane permeabilization (MMP) and the

aperture of PTP (permeability transition pore) are a point of no return in the mitochondrial pathway by activating both

caspase-dependent and caspase-independent mechanisms that eventually execute cell death. Protein cytochrome c is released

into the cytosol and interacts with the adaptor protein apoptotic peptidase activating factor 1 (APAF) as well as with pro-

caspase 9 to form the apoptosome. This results in the sequential activation of caspase 9 and executioner caspases, such as

caspase 3, a process that is known as the caspase cascade. Other pro-apoptotic proteins, such as AIF and smac/diablo, could

also be released by the mitochondria. Finally, DNA damage could also modulate the induction of Bcl2 pro-apoptotic proteins

such as BAX and BAK, which favors the apoptotic process.

Camins, Sureda, Junyent, Verdaguer, Folch, Beas-Zarate & Pallas

Expert Opin. Investig. Drugs (2010) 19(5) 589

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caspase in neurons is caspase 3, for which a key role in DNAfragmentation has been demonstrated [12]. However, the pic-ture is further complicated by evidence that caspase inhibitorsattenuate or delay neuronal cell death but do not preventit. These findings indicate that additional, mitochondria-independent, routes are involved in neuronal cell death. Inaddition, mitochondria may release other pro-apoptotic pro-teins, which, by themselves, regulate a caspase-independentapoptotic pathway such as the apoptosis inducing factor(AIF), endonuclease G and the second mitochondria-derivedactivator of caspase Smac/DIABLO [12,13]. In fact, the activa-tion of the classic apoptotic pathway is not clear in humanpatients with neurodegenerative diseases, as has been pro-posed by some authors in AD [16]. Activation of upstream cas-pases 8 and 9 has been described in AD, but activation ofeffector caspases is controversial. Lack of the terminal phasesof apoptosis, like blebbing or chromatin condensation, hasled to the concept of ‘abortosis’, a term that describes theapparently lack of apoptosis progression in AD [16,17]. How-ever, other authors have described an early activation ofcaspase 3 that disappears in more advanced phases of thedisease [18]. Therefore, some authors have suggested thatactivation of caspase 3 would be an early marker of AD [19].

3. Antiapoptotic drugs

3.1 HuperzinesHuperzine A (HupA) is an alkaloid derived from the Chineseplant Huperzia serrata. It acts as a potent and selectiveacetylcholinesterase (AchE) inhibitor and also has antiapop-totic and neuroprotective properties (Figure 2) [20-26]. Previousstudies in humans and animal models indicate that HupA ismore potent and more selective than other AchE inhibitorsand has fewer adverse effects. Interestingly, in addition topotent AchE inhibition, HupA exerts multiple actions onseveral molecular targets, including the modulation ofb-amyloid peptide processing, the reduction of oxidativestress, and glutamate toxicity, which has also been implicatedin AD [22-24]. Given the mechanisms proposed for the patho-genesis of AD, these protective properties are noteworthy.Plaques, formed by the accumulation of b-amyloid, are con-sidered a signature lesion in patients with AD and have beenshown to cause neurodegeneration. Collectively, these experi-mental data have encouraged the initiation of clinical trialswith HupA, which have demonstrated a significant enhance-ment of memory processes in patients with AD. Moreover,a Phase II clinical trial has recently been completed in theUSA. Although the results have not yet been published, thisstudy may provide new information and corroborate theusefulness of HupA in AD [8,20].

3.2 Lithium and GSK-3b inhibitorsThe mood-stabilizing effects of lithium are well documented.Thus, the main clinical application of this compound iscurrently for the treatment of bipolar disorders [27]. However,

recent experimental data indicate that lithium also exerts neu-roprotective effects by preventing programmed neuronal celldeath in several apoptotic models, such as glutamate-induced excitotoxicity, b-amyloid, H2O2-mediated oxidativestress, and 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP)toxicity [27-36]. In all these studies, lithium showed an antia-poptotic effect by inhibiting the mitochondrial apoptoticpathway and the effector caspase 3. Likewise, recent studieshave demonstrated that lithium inhibits other targets, suchas CDK5 and calpain, and also modulates NMDA receptorby preventing an increase in intracellular calcium [27]. Accord-ingly, although lithium shows a narrow therapeutic margin, itcould be used to treat neurodegenerative diseases.

Experimental research has demonstrated that when lithiumis administered at therapeutic concentrations (1 -- 2 mM), itsneuroprotective effects are exerted mainly through the inhibi-tion of glycogen synthase kinase-3 (GSK-3) [34,35]. However,this drug also activates AKT, a component of a pro-survivalpathway. This activation could also constitute an additionalexplanation for the neuroprotective effects exerted by lith-ium [27]. Although in vitro and experimental in vivo studiessupport a putative role of lithium in the treatment of neurode-generative disorders, the clinical application of this drug for ADand other neurodegenerative disorders is still unclear. Forexample, a recent clinical trial (in 71 patients) demonstratedthat the administration of lithium to AD patients does notimprove cognitive symptoms or reduce GSK-3 activity [30].Therefore, the efficacy of lithium in AD was questioned. More-over, in another clinical study, AD patients treated with lithiumfor 10 weeks showed a significant increase in brain-derived neu-rotrophic factor (BDNF) serum levels, which was accompaniedby improved cognitive function [31].

Another hypothesis holds that the potential therapeutic bene-fits of lithium are due to the induction of autophagy [33]. A phys-iological process involved in the degradation of proteins,autophagy also removes unwanted damaged cell structures ororganelles. In this case, the action of lithium in autophagy wasGSK-3-independent and research showed a prominent role ofinositol monophosphatase (IMPase) inhibition [29,33]. A recentclinical study in human patients found that lithium administra-tion slows the progression of ALS [33]. The beneficial effect ofthis drug was attributed to the activation of autophagy. Sincethis process is a major degradation route for aggregate-prone proteins associated with neurodegenerative disorders, itsinduction by lithium may also be a valuable strategy in the treat-ment of neurodegenerative diseases. Interestingly, it has beendemonstrated that bipolar patients receiving lithium (continuoustreatment during a mean of 71.2 months) were less prone to suf-fer from AD than bipolar patients who were not treated with thisdrug [34]. This observation indicates that lithium has beneficialeffects in clinical trials [34]. Therefore, it is clear that morelong-term clinical trials with this drug in AD are required inorder to establish its efficacy in preventing or delaying the pro-gression of this disease. In addition, lithium is currently beingtested in clinical trials on progressive supranuclear palsy [27].

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Given that GSK-3 is a suitable target to inhibit apoptosis,recent years have witnessed considerable research effortdevoted to the identification and development of GSK-3inhibitors [28]. In this regard, several chemically diversefamilies have emerged, including inhibitors such as paul-lones, indirubines, thiazoles, aminopyrimidines and bisindol-maleimides. Most of these, however, are ATP-competitiveinhibitors [35]. For instance, there is wide experience inthe use of the maleimide derivatives SB-216763 and SB-41528, developed by GlaxoSmithKline. These two com-pounds are potent GSK-3 inhibitors in vitro and haveneuroprotective effects in several models of neurotoxicity(Figure 2). The 2-aminothiazole AR-A014418, developedby AstraZeneca, is another ATP-competitive inhibitor.This drug was found to be neuroprotective in experimentalmodels of AD [36].

3.3 Anti-inflammatory drugsThe application of anti-inflammatory drugs has been pro-posed as another strategy to improve cognitive function inAD and to prevent neuronal cell loss. These drugs may exerttheir beneficial effect by inhibiting the inflammatory cascadein the brains of AD patients [37]. The b-amyloid cascadehypothesis holds that the accumulation of amyloid in senileplaques triggers a pathological cascade that results in neuronaldysfunction and death. In addition to b-amyloid deposition,an inflammatory response is also generated by neurofibrillarytangle accumulation. Thus, positive feedback is initiated asinflammation promotes both increased b-amyloid productionand enhanced deposition. Given that the inflammatoryresponse to b-amyloid is harmful, anti-inflammatory drugshave been proposed as beneficial agents in AD therapy [38].However, recent studies indicate that NSAIDs have other

NH

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Istradefylline

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HN O

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Huperzine A

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Figure 2. Chemical structures of neuroprotective compounds discussed in the paper.

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antiapoptotic effects against b-amyloid-induced toxicity inneuronal cell cultures. b-amyloid oligomers cause mitochon-drial depolarization, which is prevented by NSAIDs throughthe inhibition of mitochondrial calcium overload [38-40].Moreover, by preventing ROS production and inhibitingCyt c release, these drugs might exert an antiapoptoticeffect [38,40].Accordingly, the preservation of mitochondrial function

has been proposed as the main mechanism of action throughwhich NSAIDs exert neuroprotection. These hypotheses weresupported by the finding that learning impairments inTg2576 APP mice were attenuated by chronic treatmentwith R-flurbiprofen (Figure 2) [39]. On the other hand, it hasbeen proposed that the antiapoptotic effects of R-flurbiprofenand others anti-inflammatory drugs could be due to anincrease in neurotrophin production [39]. The finding favorsthe use of this drug in the treatment of AD. Although theresults of clinical trials of NSAIDS have so far been discourag-ing, more clinical trials with R-flurbiprofen are necessary tounderstand how this drug and others NSAIDs could preventcognitive decline in patients with AD and might promoteneurotrophin upregulation [41,42].

3.4 LeptinLeptin is an endogenous hormone that physiologically con-trols feeding behavior through the activation of specific recep-tors in the hypothalamus. Thus, this hormone is crucial to theregulation of fat storage and mobilization. However, recent

data demonstrate that leptin regulates the phosphorylationof GSK-3b at Ser-9 [43]. This regulation leads to the deacti-vation of this kinase and to a reduction in tau phosphoryla-tion, which, as previously commented, is a key feature in ADand a possible target for treatment of this disease [44]. Inaddition, leptin modulates the production of b-amyloid.For instance, chronic administration of leptin in mousemodels of amyloid-b precursor protein (AbPP) overexpres-sion (Tg2576) significantly reduces brain amyloid concen-tration levels [43-45]. Interestingly, leptin levels are associatedwith a reduced incidence of AD [46], and leptin administrationimproves cognitive performance in a transgenic mouse modelof AD [47]. These and other experimental data support a clinicaltrial for leptin as a potential novel therapy for AD. However,there is no further evidence of a therapeutic effect of this drugin neurodegenerative disorders.

3.5 Bile acidsUrsodeoxycholic acid, an endogenous bile acid, and its tau-rine conjugate, tauroursodeoxycholic acid (TUDCA), arepotent inhibitors of neuronal apoptosis in several paradigmsof excitotoxicity, AD, PD and Huntington’s disease (HD)in neuronal cell preparations [48]. Furthermore, the protectiverole of TUDCA has been demonstrated in several mousemodels of neurological disorders, including HD, PD andacute ischemic insult. TUDCA inhibits b-amyloid-inducedmitochondrial alteration and pro-apoptotic protein release inisolated neuronal mitochondria [48-50]. Moreover, by electron

N

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H H

OH

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OH

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Minocycline

HN

CH

Rasagiline

HO

OH

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Resveratrol

HN

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N

Cl

Cl

SB-216763

OH NH

SO3H

HOH

H

H H

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O

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Tauroursodeoxycholic acid

Figure 2. Chemical structures of neuroprotective compounds discussed in the paper (continued).

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paramagnetic resonance spectroscopy analysis, it was demon-strated that TUDCA prevents b-amyloid-driven modifica-tions in mitochondrial membrane redox status, lipid polarityand protein conformation. The effects of TUDCA on mito-chondria affected by b-amyloid deposition were confirmedby the observation of decreased Bax translocation and induc-tion of channel formation in the presence of this bile acid.Furthermore, TUDCA inhibits the effects of b-amyloidon the expression of cell cycle proteins and p53 [49,51,52].Accordingly, bile acids are antiapoptotic compounds that acton mitochondria by preventing the release of pro-apoptoticproteins and subsequent activation of caspase 3 and also thepro-apoptotic p53 pathway [48].

3.6 Antioxidants as apoptotic inhibitorsThe contribution of antioxidants to the prevention of neuro-degenerative diseases is controversial. The main advantage ofthese agents is their safety and tolerability. A number of anti-oxidant molecules have been postulated to be useful in theprevention and/or treatment of neurodegenerative diseases,e.g., vitamin E, melatonin, resveratrol, carnosine, and coen-zyme Q10 [53-58]. All these antioxidant drugs show neuropro-tective effects against b-amyloid accumulation and otherneurotoxins in neuronal cell cultures. Experimental data arenow available for several antioxidant compounds, andresearch on the administration of dietary vitamins E and Chas been conducted in humans [57]. One clinical study indi-cated that in patients with moderately severe AD, the admin-istration of vitamin E delayed disease progression, thusproviding evidence of the beneficial effects of this vitaminwhen included in AD treatment [57]. In keeping with theseresults, other studies on the administration of vitamin C,carotenoids and other antioxidants to AD patients haveshown that these antioxidants also have a protective effectagainst this disease [56]. Data published on vitamin E do notsupport the efficacy of this vitamin in the prevention or treat-ment of subjects with AD or mild cognitive impairment(MCI) [54]. Furthermore, although vitamin E may decreaseoxidative stress in some AD patients, it impairs cognition inothers. Therefore, more research is required to determinethe contribution of vitamin E alone or in combination withother drugs in the management of cognitive impairmentin AD.

3.6.1 Ginkgo bilobaThe compound ginkgo biloba (EGb) 761 is an extract fromleaves of a unique species of tree, Ginkgo biloba [59]. EGb761 is a potent antioxidant and scavenger of free radicals; itinterferes with glutamatergic NMDA receptor. EGb 761 isused as a natural dietary supplement for memory enhance-ment [60]. The protective action of this compound on neuro-nal survival may be attributable to its antioxidant properties.This notion is supported by evidence that EGb 761 showsprotective effects against H2O2-induced toxicity. Likewise,EGb 761 inhibits b-amyloid neurotoxicity by reducing

oxidative stress [59,60]. In addition, this compound exerts sev-eral actions on mitochondrial function and on the apoptoticpathway, such as stabilizing the improvement in energymetabolism, increasing the levels of antiapoptotic proteinslike Bcl-2, and decreasing the expression of the pro-apoptoticBax [61,62]. Moreover, this extract inhibits the release of Cyt cand the activation of caspase 3. Furthermore, EGb 761 indu-ces an increase in a APPs secretion in vivo and in vitro [63,64].All these beneficial effects remain to be demonstrated inhuman neurodegenerative diseases. Thus, the oral administra-tion of ginkgo biloba partially reverses the memory deficitthrough its effect on the cholinergic system [64,65]. However,DeKosky and co-workers were unable to find any beneficialeffect of a ginkgo biloba extract in patients with MCI [66].Again, it is expected that more data from ongoing trials willshed more light on the therapeutic benefits of this extractfor the treatment of neurodegenerative diseases.

3.6.2 MelatoninMelatonin is a well-tolerated compound that has been mar-keted as a nutritional supplement in several countries [67-69].It has multiple actions as a regulator of antioxidant enzymesand, by itself, acts as a radical scavenger. The antiapoptoticeffects of melatonin could be explained by its mitochondrialand non-mitochondrial effects. For example, melatonin pre-vents the formation of cdk5/p25 and oxidative stress-inducedmitochondrial calcium overload, mitochondrial depolariza-tion, ROS formation, and the opening of the mitochondrialPTP that precedes Cyt c release [69]. Indeed, a potent neuro-protective effect has been described against b-amyloid toxicityin neuronal cell cultures. Moreover, studies in vivo using atransgenic mouse model of AD showed that melatoninadministration is associated with cognitive and behavioralbenefits (possibly involving the prevention of b-amyloidaggregation), as well as with anti-inflammatory and anti-oxidant effects [69-72]. Moreover, melatonin attenuatessuperoxide-induced cell death and modulates glutamatetoxicity in cultured neurons [69]. Melatonin might be usefulin other conditions, as shown by results of studies using neu-rotoxins, such as 3-nitropropionic acid (3NPA) in rats (ananimal model of HD) and in experimental models ofPD [68,69]. This compound has an antiageing effect [71]. Inaddition, it extends the survival of mutant SOD1 (G93A)ALS transgenic mice and delays disease progression in theseanimals. Collectively, all these experimental data providesupport for long-term melatonin therapy as a primary orcomplementary strategy in the prevention of neurodegenera-tive disorders [70]. Although only a few clinical studies havebeen carried out with this compound, a recent study reportsthat patients with MCI treated with 3 -- 9 mg melatonindaily showed a significant improvement in cognitive func-tion [73]. However, the potential of melatonin as an anti-dementia drug, or its application in neurological disordersalone or in combination with other drugs, requires furtherstudy. Furthermore, the administration of melatonin has

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been shown to cause decreased oxidative damage in patientswith sporadic ALS. Taken together, the large body of evi-dence supports that melatonin, through its mitochondria-dependent antiapoptotic activities, could exert a potentialneuroprotective effective in ALS, AD, HD and PD [69].

3.6.3 ResveratrolAttention has turned to resveratrol (RESV), a naturally-occurring polyphenol with strong antioxidant properties thatis abundant in red wine [74]. Recent studies indicate thatRESV-induced neuroprotection is related to an antiapoptoticmechanism that is independent of its antioxidant properties.RESV acts as an agonist of sirtuins (also called SIRT [silentinformation regulator two] proteins), which belong to the his-tone deacetylase family [75,76]. Current research is thereforefocusing on the mechanisms underlying the capacity ofRESV to increase SIRT1 activity and the intracellular path-ways activated or regulated by this compound. Recent studiessupport the notion that SIRT1 mediates intracellularresponses that promote cell survival, enhance the repair ofdamaged DNA and reduce cell division [74-76]. Studies havereported that SIRT1 exerts its neuroprotective effects bydeacetylating transcription factors, such as the tumor suppres-sor p53, the FOXO family (also called FKHR, a member ofthe Forkhead family of transcription factors, where it preventsthe nuclear translocation and activation of its targets, such asBIM), the transcription factor NF-kB and Ku70, therebyreducing their capacity to trigger apoptosis [77-80]. The poten-tial link between RESV and AD is also supported by studiesshowing that moderate consumption of red wine is associatedwith a lower incidence of AD and improved neuropathologyin a mouse model of the disease [79]. A number of studiesin vitro and in vivo have examined the molecular neuroprotec-tive mechanisms associated with RESV. b-Amyloid peptideinduces cell death through apoptosis in many cell types viaROS, and this effect is also blocked by RESV [78,80,81]. Like-wise, the neuroprotective effects of RESV have been demon-strated in various experimental models of ischemia, PD andHD [80-82]. The administration of a diet containing RESVor treatment with RESV to adult mice prior to treatmentwith the neurotoxin MPTP has neuroprotective effects ondopaminergic neurons [82]. Furthermore, studies in vitrohave also demonstrated the neuroprotective effects ofRESV against a number of neurotoxins [81]. However, ithas been suggested that SIRT1 activation does not play amajor role in the protective effect exerted by RESV againstMPP+-induced cytotoxicity, because sirtuin inhibitors, suchas nicotinamide and sirtinol, do not counteract the neuro-protection exerted by this polyphenol [83]. In contrast,authors working in this field conclude that antioxidantactions are responsible for the neuroprotective action ofRESV against MPP+-induced cytotoxicity [81-83].It has been postulated that RESV has beneficial effects on

life span and prevents memory impairment by activatingSIRT1 [74]. However, a recent study in a mouse model of

AD showed that RESV does not increase activation ofSIRT1. Therefore, these data could be explained by a mecha-nism independent of SIRT1 activation [74-76,81]. However,more studies are required to clarify whether these effects aremediated by SIRT1 activation or whether they are depen-dent on the antioxidant properties of RESV or on otherpotential mechanisms.

3.7 RasagilineRasagiline (N-propargyl-[1R]aminoindan) is a monoamineoxidase (MAO) B inhibitor (Figure 2). It has been proposedthat this drug is effective and useful for the treatment of neu-rodegenerative diseases, since it inhibits apoptosis at multiplepoints [84]. Rasagiline prevents mitochondrial depolarization,the release of pro-apoptotic proteins, and the activation ofcaspase 3 [85-87]. The main mechanism to explain the partici-pation of rasagiline in mitochondrial membrane stabilizationis unclear; however, it upregulates antiapoptotic proteinssuch as Bcl-2 and Bcl-xL and decreases the expression ofpro-apoptotic molecules, like Bax [87]. All these actions maycontribute to the modulation of mitochondrial architecture.Furthermore, these effects on mitochondria could explainthe neuroprotective effects of this drug in vitro againstglutamate in neuronal cell cultures, 6-hydroxydopamine(6-OHDA), MPP+ and b-amyloid. Interestingly, recent stud-ies indicate that this compound also exerts a neurotrophiceffect through the activation of the tyrosine kinase receptorsignaling pathway [85-87]. Likewise, rasagiline activates thePI3K pathway, which is involved in cell survival throughAkt/PKB upregulation and inactivation of GSK-3b. SinceGSK-3b inhibitors are used to treat AD (see above), theseresults indicate that rasagiline has a potential application inneurodegenerative diseases [87].

Clinical results for this drug are encouraging. A recentstudy reported that treatment with rasagiline at a dose of1 mg/day to PD patients improves symptoms and even modi-fies the progression of the disease. In general, this drug did notcause serious side effects in monotherapy [88]. However, giventhat the treatment of neurodegenerative diseases probablyrequires the co-administration of several drugs, the pharmaco-kinetic interactions of rasagiline with other drugs shouldbe examined.

3.8 Coenzyme Q10Coenzyme Q10 (CoQ10) is another compound that haspotential neuroprotective application in neurodegenerativediseases (Figure 2) [89]. An endogenous pro-enzyme foundin the inner mitochondrial membrane, CoQ10 participatesin a series of enzymatic reactions involved in oxidativephosphorylation in the respiratory chain [89-93].

Lack of CoQ10 in humans may cause diseases by one ormultiple processes, including reduced respiratory chainactivity and enhanced ROS production. Therefore, it hasbeen hypothesized that a decrease in the levels of CoQ10and in complex I activity is involved in the pathogenesis of

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PD [89,92-95]. Likewise, since neurodegenerative diseases arecharacterized by defects in the inner mitochondrial membraneand in oxidative phosphorylation, CoQ10 could be useful forthe treatment of all neurodegenerative diseases [89,96,97].

In this context, CoQ10 therapeutic applications have beenevaluated in clinical studies in PD and HD patients. Lowerconcentrations of CoQ10 and decreased complex I activitywere found in the brains and platelets of PD patients comparedwith matched controls [97,98]. Thus, it was hypothesized thatCoQ10 potentially slows deterioration in the nigrostriataldopaminergic system [92-94]. Other trials in patients withFriedreich’s ataxia showed significant improvements in coronarysymptoms [98]. However, neurological dysfunctions were notameliorated after treatment with 5 mg/kg/day CoQ10. Clinicaltrials with AD patients have not been published to date.

3.9 Adenosine A2 receptor antagonistsAs we discussed above, the dopamine precursor L-DOPA(L-3,4-dihydroxyphenylalanine) and dopaminergic receptoragonists are the drugs used in the treatment of PD [99,100].Other drugs include cholinolytic compounds; namely thecatechol-O-methyltransferase inhibitors (COMTs). Previousstudies suggest that adenosine A1 and A2A receptors play arelevant role in neuroprotection. This notion arose from pre-vious studies which showed that caffeine has neuroprotectiveeffects in an animal model of MPTP-induced PD [101]. Thiseffect was attributed to the blockade of adenosine receptors,mainly A2. Subsequently, in this context, istradefylline wasdeveloped [99]. This drug shows neuroprotective effects andthus may be a suitable candidate for the treatment of PD.Istradefylline is a selective adenosine A2A, showing 70 timesgreater selectivity for A2A than for adenosine A1 recep-tor [101,102]. Experimental studies have corroborated the bene-ficial effects of this compound in experimental models ofPD [99]. Istradefylline lowered the extrapyramidal mobilitydisorders caused by MPTP in monkeys. Moreover, inhibitionof adenosine A2A receptor in striatum potentiates the dopaminerelease from neurons when L-DOPA is administered [101-103].The mechanism involved in the neuroprotection exerted bythis drug could be associated with the prevention of glutamaterelease, as it is well known that glutamate plays a prominentrole in neuronal death though the excitotoxic process. Theadministration of istradefylline to humans is safe and increasesthe efficacy of L-DOPA in PD patients. Thus, as humanclinical trials suggest, istradefylline may increase the therapeuticefficacy of L-DOPA and have a positive effect in early-stage PD. Accordingly, istradefylline might delay the progres-sion of PD symptoms [103]. However, the neuroprotectiveaction of this drug on dopaminergic neurons remains to beconfirmed in this neurodegenerative disorder.

3.10 MinocyclineMinocycline is a tetracycline derivative that has several differ-ential features. It is more lipophilic than other tetracyclines,meaning that it can cross the blood--brain barrier. In addition,

it shows anti-inflammatory properties, apparently through themodulation of immune chemical mediators like chemokinesand cytokines [104]. In fact, this drug has been authorized forthe treatment of rheumatoid arthritis.

However, the most striking feature of minocycline com-pared with other tetracyclines is that it shows neuroprotectiveproperties in several animal models of neurodegenerativediseases, such as ALS, AD, HD and PD [105-108]. This drugexerts neuroprotective activity through a number of pathways.Several reports indicate that it decreases the activation of theintrinsic apoptotic pathway. It also increases the expressionof the antiapoptotic protein Bcl-2 and inhibits caspase 1 and-2 expressions [106]. Moreover, minocycline acts upstream ofmitochondria, and the protective effects also might bethe result of p38 inhibition, which would explain both itsneuroprotective and immunomodulatory action [105-107].

The neuroprotective effect of minocycline in several animalmodels of neurodegenerative diseases has brought about clin-ical trials. In fact, in small clinical trials this drug has shownbeneficial effects in HD and PD [109]. Several other Phase IIand III assays are currently underway to ascertain the benefitsand safety of this drug in neurodegenerative diseases and inother conditions, such as stroke, HIV+ cognitive impairment,and spinal cord injury [108-110].

However, several concerns have been raised regarding theefficacy of minocycline. Some studies did not find a neuro-protective effect in vitro or in animal models of HD orAD [105-108]. Furthermore, the adverse effects of long-termtreatment with minocycline are of particular concern [108].Moreover, recent findings from an ALS study show thatminocycline worsened this condition [110]. Results fromthe cited ongoing studies are expected to clarify thepotential of this compound for the treatment ofneurodegenerative diseases.

3.11 CEP-1347 or inhibitors of the JNK pathwayAn interesting pathway activated in the apoptotic process inneurons is the JNK/stress-activated protein kinase (SAPK)pathway [111,112]. Accordingly, it has been proposed that inhi-bition of this pathway would be a promising strategy in thedevelopment of drugs for the treatment of neurodegenerativedisorders. A highly relevant component of this cascade is themixed-lineage kinase (MLK) family of kinases, which activatesa neuronal cell death signal transduction pathway. JNKbelongs to the MAPK family and the following three groupsof MAPKs have been identified in mammalian cells: JNKs(also known as the SAPKs), p38 MAPKs, and ERKs. Threegenes encode JNK protein kinases, namely Jnk1, Jnk2 andJnk3. While the first two are widely expressed, Jnk3 isexpressed only in brain, heart, and testis. Interestingly,JNK3 may play a relevant role in neuronal cell death [111-114].This hypothesis is based on the evidence that a Jnk3-deficientmouse model is protected against neurotoxicity modelsinduced by kainic acid and also by MPTP [113]. JNKhas numerous substrates; however, c-jun, one of the first

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substrates identified for this kinase, merits the greatest atten-tion. Interestingly, there is increasing evidence that JNKdirectly phosphorylates and regulates the pro- and antiapop-totic activity of members of the Bcl-2 family. JNK phosphor-ylates and decreases the antiapoptotic activity of both Bcl-2and Bcl-XL. In addition, this kinase phosphorylates the pro-apoptotic protein BAD at Ser-128, thereby potentiating itspro-apoptotic effect [114]. Similarly, JNK phosphorylates thepro-apoptotic proteins Bim and Bmf, thereby causing theirrelease, with translocation to mitochondria, followed byrelease of mitochondrial pro-apoptotic death mediators.Thus, by acting through both transcriptional and non-transcriptional mechanisms, JNK is a key apoptotic mediatorof neuronal cell death.Regarding potential drugs with antiapoptotic effects,

CEP-1347, an inhibitor of MLKs, shows neuroprotectiveeffects both in vitro and in vivo against b-amyloid toxicity,trophic withdrawal in PC12 cells, apoptosis in cerebellargranule cells mediated by serum and potassium deprivation,and MPP+ exposure [112-116]. Furthermore, CEP-1347 showsneuroprotective effects in the experimental model of Parkin-sonism mediated by the neurotoxin MPTP and also againstapoptosis induced by cytoskeletal disruption [112,113]. More-over, in addition to inhibiting the pro-apoptotic JNK path-way, this drug activates neurotrophic pathways, includingthe neurotrophin BDNF in a mouse model of HD [111]. Inaddition, this antiapoptotic agent has shown promisingresults in preclinical studies. However, although initial clin-ical trials demonstrated that the administration of CEP-1347 twice daily was safe and well tolerated in a randomizedplacebo-controlled study in PD subjects, in the later PRE-CEPT clinical trial, it was concluded that CEP-1347 wasnot effective for the treatment of this neurodegenerativedisorder [117,118].

3.12 Other potential drugsGlatiramer acetate (Cop-1, copolymer-1 or copax-1) is a syn-thetic, random oligopeptide comprising tyrosine, glutamate,lysine and alanine residues. Glatiramer acetate is an FDA-approved drug for the treatment of multiple sclerosis [119].This drug exerts several effects on T cells, thereby increasingcytokine release. Interestingly, exposure of lymphocyte cellsto glatiramer acetate leads to increased secretion of the potentneurotrophin BDNF. BDNF exerts antiapoptotic effects in avariety of experimental models of neurodegenerative diseasesby activating pro-survival pathways (Akt). Consequently, itis hypothesized that this compound exerts neuroprotectiveactions in neurodegenerative diseases [12].Another strategy to prevent neuronal apoptosis is by

impeding cell cycle re-entry. A common feature of neurode-generative diseases is that neurons increase the expression ofcell cycle proteins such as cyclin-dependent kinases (cdk4,cdk2), cyclins (cyclin D and cyclin E) and the pro-apoptotic(in neurons) transcription factor E2F-1. Therefore, it hasbeen proposed that antitumoral drugs, such as flavopiridol,

have some potential in the treatment of neurodegenerativedisorders [120]. However, the safety and tolerability of thesecompounds are matters of concern.

Valproic acid is another interesting drug with demon-strated antiapoptotic effects. Clinical trials in AD andothers neurodegenerative disorders are currently underway(Table 1) [121].

4. Conclusions

Over recent decades, several clinical trials have been carriedout to determine the efficacy of neuroprotective drugs inneurodegenerative diseases. However, although preclinicalstudies have provided promising results, only a very limitednumber of compounds have been authorised by regulatoryagencies, as many of these compounds did not show effi-cacy. A number of factors might contribute to this apparentloss of effect in a clinical setting. First, it is possible that thestage of disease shown by patients included in clinical trialswas too advanced for the drug to provide a measurableeffect. In other words, the drug was administered too late.Thus, this limitation is clearly related to our ability to diagnosea neurodegenerative disease in its earliest stages. Althoughmany efforts have been made in this regard, analytical param-eters that constitute markers of a particular neurodegenerativedisease are still unavailable. Moreover, there is a consensusthat it is necessary to preserve mitochondrial function toobtain suitable neuroprotection in experimental modelsin vitro. The alteration of mitochondria and opening of thePTP constitutes the point of no return, and the process ofcell death cannot be reversed. A similar event may also occurin humans, and the drugs used in clinical trials may havebeen administered when this mitochondrial dysfunction wastoo advanced.

The clinical development of neuroprotective compoundsmay also be hampered because apoptosis is not the onlymechanism through which neurons die. Other mechanisms,such as necrosis and autophagia, may account for the deathof this cell type. Experimental models of neuronal deathprovide some examples in which pan caspase inhibitors,such as z-VADfmk, delay neuron death; however, these cellsthen die through an apoptotic caspase-independent process.These observations lead to the hypothesis that therapeuticintervention should act on several pathways that triggerneuronal loss. An example would be cancer treatment (obvi-ously depending on the type of cancer) that employs morethan one drug or therapeutic strategies such as alkylatingagents, monoclonal antibodies and radiation. A similarstrategy may need to be followed in future for the treatmentof neurodegenerative diseases. Likewise, another approachwould be to search for a drug that inhibits more than onepathway or shows several beneficial properties, such as anti-oxidant or antiapoptotic (mitochondrial) effects, in additionto inhibiting key enzymes in pathways such as those of JNKand GSK-3.

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Table

1.Clinicalstudieswithseveraldrugsforthetreatm

entofneurodegenerativediseases.

Disease

Drug

ClinicalTrials.gov

Identifier

Status

Start

date-

Completiondate

Sponso

r/Collaborators

Phase

Observations

Alzheim

er’sdisease

R-flurbiprofen

(MPC-7869,

Tarenflurbil)

NCT00105547

Completed

Feb2005-M

ay2008

MyriadPharm

aceuticals

IIIDiscontinued

developmentdue

tolack

ofcognitive

improvement

Valproic

acid

NCT00071721

Ongoing

Oct

2003-Oct

2008

Natl.Inst.onAging

IIIResveratrol

NCT00743743

Notyetopen

Sept2008-Dec2010

MedicalCollegeof

Wisconsin

III

NCT00678431

Ongoing

Jan2008-June2011

Dept.VeteransAffairs

IIICo-administered

withglucose

and

malate

asa

nutritional

supplement

HuperzineA

NCT00083590

Completed

April2004-Nov2007

Natl.Inst.onAging

IIAmyotrophic

lateral

sclerosis

Minocycline

NCT00047723

Completed

Jan2003-Jan2007

Natl.Inst.ofNeurol.

Disord.andStroke

IIIMinocycline

actually

worsens

thedisease

[98]

Lithium

NCT00818389

Term

inated

Jan2009-O

ct2009

MassachusettsGen.

Hosp./NINDS

II/III

Glatirameracetate

NCT00326625

Completed

June2006-July2008

Teva

Pharm

aceutical

Industries

II

Tauroursodeoxy-cholic

acid

NCT00877604

Recruiting

June2008-Dec2010

Univ

Palerm

o(Italy)

II

Huntington’s

disease

CoenzymeQ10

NCT00608881

Recruiting

March2008

Massachusets

General

Hospital/NINDS

III

Minocycline

NCT00277355

Ongoing

Jan2006-O

ct2008

HuntingtonStudyGroup/

FDA

officeoforphan

productsdev

II/III

NCT00029874

Completed

Sept2001-Aug2003

FDA

OfficeofOrphan

Prods.

Dev

I/II

Multiple

sclerosis

Epigallocathechin

gallate

NCT00525668

Recruiting

Sept2007-Dec2011

Charite

University,

Berlin,

Germ

any

I/II

Administeredasa

greenteaextract

Multisystem

atrophy

Minocycline

NCT00146809

Completed

Dec2003-Dec2005

Germ

anPDStudygroup

IIINopositive

effect

ondisease

progression

[24]

Lithium

NCT00997672

Notyetopen

Oct

2009-Nov2011

Federico

IIUniversity

(Naples,

Italy)

II

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Table

1.Clinicalstudieswithseveraldrugsforthetreatm

entofneurodegenerativediseases(continued).

Disease

Drug

ClinicalTrials.gov

Identifier

Status

Start

date-

Completiondate

Sponso

r/Collaborators

Phase

Observations

Parkinson’s

disease

Rasagiline

NCT00696215

Recruiting

June2007-O

ct2008

IstambulUniversity

IVCoenzymeQ10

NCT00740714

Recruiting

Dec2008-Sept2011

WeillMedicalCollege

(CornellUniv.)/NINDS

III

NCT00180037

Completed

Sept2003-June2005

DresdenUniv.of

Technology

IIIWelltolerated,but

doesnotdisplay

symptomatic

effects

Rasagiline

NCT00256204

Ongoing

Nov2005-June2009

Teva

Pharm

aceutical

Industries

IIIPossible

disease-

modifyingeffect,

butdata

are

not

conclusive

[76]

Istradefylline

IIISeveralstudies

have

carriedoutto

assess

beneficial

effectsin

PD,but

noneisdesignedto

demonstrate

aneuroprotective

effect

CEP-1347

NCT00040404

Term

inated

March2002

Cephalon/Lundbeck

II/III

Noeffect

on

disease

progression

[105]

Isradipine

NCT00909545

Recruiting

July2009-July

2012

TheParkinsonStudy

Group

II

Minocycline

NCT00063193

Completed

May2003-July

2005

Univ.Rochester/Natl.Inst.

ofNeurol.Disord.and

Stroke

IICo-administered

withcreatine.

Somebeneficial

effects[97]

Progressive

supra-nuclear

palsy(PSP)

CoenzymeQ10

NCT00382824

Recruiting

Sept2006-Sept2012

LaheyClinic

(Burlington,

MA,USA)

II/III

Valproic

acid

NCT00385710

Ongoing

Nov2006-Aug2010

NantesUniv.Hospital

(France)

II

PSPorcortico-basal

degeneration

Lithium

NCT00703677

Recruiting

Sept2008-Sept2009

Westat/Natl.Inst.of

Neurol.Disord.and

Stroke

I/II

PSPandcortico-basal

degeneration

CoenzymeQ10

NCT00532571

Completed

Jan2004-Sept2005

LaheyClinic

II/III

Mild

cognitive

impairment

Melatonin

NCT00544791

Recruiting

Oct

2007-O

ct2010

Assaf-HarofehMedical

Center/Neurim

Pharm

aceuticals

II

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5. Expert opinion

The development of neuroprotective drugs is undoubtedly anarea of increasing relevance for the pharmaceutical industry,mainly because of the perspective of a high incidence andprevalence of neurodegenerative diseases in the near futureand the inadequate efficacy of current treatments. Althoughthe search for new and effective drugs is taking longer thaninitially expected, it is especially encouraging that the com-pounds currently under investigation act through a widevariety of mechanisms. A key point that limits success in thedevelopment of new drugs is that the exact mechanism behindneuronal cell death is not known. This complex processinvolves several biochemical parameters, such as oxidativestress, mitochondria, pathways of cell cycle activation, DNAdamage, cytoskeletal alteration, the activation of enzymessuch as GSK-3 and JNK, and AKT inhibition. However, amajor concern in the development of novel therapies for thetreatment of neurodegenerative diseases is their safety inhumans. For instance, lithium is an interesting candidate forfurther development as a neuroprotective agent, since itappears to act on more than one signaling pathway duringneuronal cell death. It increases the activity of pro-survivalpathways such as AKT and has antioxidant properties directlyor indirectly through the upregulation of antioxidantenzymes [19]. Clinical trials are encouraging, but it should bekept in mind that this drug has a narrow therapeutic index,which may limit its chronic use. As this is the current situa-tion, other GSK-3 inhibitors are being developed, althoughclinical assays remain to be evaluated [26].

Melatonin has received much attention, since it is wellestablished that this endogenous compound is safe and well-tolerated in long-term administration. Furthermore, it is ahighly lipophilic compound, and unlike other antioxidants,it protects mitochondria from excessive oxidative stress. Infact, mitochondria-related damage in neurons is a primarycause of neurodegenerative diseases and mitochondriamalfunctioning clearly contribute to cognitive impairmentand memory decline. Therefore, targeting mitochondriawith antioxidants such as RESV, melatonin or other com-pounds would provide a powerful strategy to achieve neuro-protection and to preserve cognitive function [12,13]. In thiscontext, experimental data suggest that the antioxidant effectsof these compounds are also accompanied by stabilizingeffects on the mitochondria, thereby implying that thesecompounds have additional neuroprotective effects [75-82].Furthermore, the antiageing and SIRT1-activating propertiesof RESV may also contribute to its beneficial therapeuticeffects and should be studied further. However, recent datasuggest that CEP-1347 is not effective in the treatment of PD.

However, some criticisms have arisen concerning thedesign of clinical trials for these compounds. First, it may be

difficult to select the population of the patient cohort, toestablish their stage of disease, and also to achieve diagnosticaccuracy and to determine the associated cognitiveimpairment. These factors may distort the results of the studyand its outcome. Having passed the thresholds of futility anal-yses, other promising therapies (such as the tetracycline anti-biotic, minocycline) are also candidates for further testing.However, it must be considered whether the long-termadministration of an antibiotic is adequate for the treatmentof neurodegenerative diseases and the potential side effectsof these compounds. In this case, the prevention of cell deaththrough the administration of food supplements like RESV ormelatonin would be of added value.

Other arguments have been raised against the use of anti-apoptotic drugs for the treatment of neurodegenerative dis-eases. We may be able to delay the apoptotic process, whichmay slow down neuronal death, but the question remains asto whether these neurons remain fully functional. Drugsmight be useful to keep the neurons alive, but viability mightnot correlate with performance. In this regard, it is essentialthat the design of clinical trials includes measurements of cog-nitive performance in SD patients, for instance. We shouldkeep in mind that apoptosis is a physiological phenomenonthat removes cells programmed to die because they are no lon-ger useful. Another important issue to consider is the momentwhen treatment should be started. Again, if neurons are in anadvanced apoptotic phase, it is not surprising that treatmentsare ineffective.

Finally, to date, neuroprotective treatments have been lim-ited to pharmacological interventions, which generally involvesmall molecules capable of crossing the blood--brain barrier.Currently, recombinant gene therapy may widen the therapeu-tic options available. By using viral vectors, it is now possible toprovide genetic instructions to neurons or other brain cells forthe controlled production of potential disease-modifying sub-stances. This approach could open up a new strategy for thefuture treatment of neurodegenerative diseases.

Declaration of interest

This study was supported by grants from the SpanishMinistry of Education and Science SAF-2009-13093, theFondo de Investigacion Sanitaria and the Instituto de SaludCarlos III (PI080400 and PS09/01789). We thank theCatalan Government (Generalitat de Catalunya) for support-ing the research groups (2009/SGR00853) and Fundacio laMarato TV3 (063230), as well as 610RT0405 from ProgramaIberoamericano de Ciencia y Tecnologia para el Desarrollo(CYTED). E Verdaguer holds a ‘Beatriu de Pinos’ post-doctoral contract, awarded by the Generalitat. We thank theUniversity of Barcelona Language Services for revising themanuscript.

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AffiliationAntoni Camins†1 PhD, Francesc Xavier Sureda2,

Felix Junyent1,3, Ester Verdaguer1, Jaume Folch3,

Carlos Beas-Zarate4 & Merce Pallas1

†Author for correspondence1Institut de Biomedicina (IBUB),

Centros de Investigacion Biomedica en

Red de Enfermedades Neurodegenerativas

(CIBERNED),

Unitat de Farmacologia i Farmacognosia,

Facultat de Farmacia,

Universitat de Barcelona,

Nucli Universitari de Pedralbes,

08028 Barcelona, Spain

Tel: +34 93 4024531; Fax: +34 93 4035982;

E-mail: camins@ub.edu2Unitat de Farmacologıa,

Centros de Investigacion Biomedica en Red de

Enfermedades Neurodegenerativas

(CIBERNED),

Facultat de Medicina i Ciencies de la Salut,

Universitat Rovira i Virgili,

43201 Reus (Tarragona), Spain3Unitat de Bioquimica,

Facultat de Medicina i Ciencies de la Salut,

Centro de Investigacion Biomedica en Red de

Enfermedades Neurodegenerativas

(CIBERNED),

Universitat Rovira i Virgili,

43201 Reus (Tarragona), Spain4Departamento de Biologıa Celular y Molecular,

CUCBA,

Universidad de Guadalajara,

Division de Neurociencias,

Centro de Investigacion Biomedica de Occidente,

IMSS, Guadalajara,

Jalisco 44340, Mexico

An overview of investigational antiapoptotic drugs with potential application

604 Expert Opin. Investig. Drugs (2010) 19(5)

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