Download - Fang china translational_medicine
Cannabinoid in CNS Diseases: A Potential Therapeutic Target
Xiang Fang, MD, PhD.
Assistant Professor
Department of Neurology
University of Texas Medical Branch
Galveston, TX 77555
University of Iowa, IA
Harbor Hospital, Baltimore, MD
Old Red at UTMB, TX
Marijuana is the dried flowers, leaves and stems of the Cannabis sativa plant.
97.8 million Americans aged 12 or older tried marijuana at least once in their lifetimes, representing 39.8% of the U.S. population in that age group. NSDUH, 2006
• A potent drug that has strong impact on the brain and the rest of the body. • In addition to producing an intoxicating "high," marijuana can ease anxiety and pain, stimulate hunger, and impair memory. • A long history in folk medicine. It's been used for menstrual pain and the muscle spasms associated with multiple sclerosis.
CB1 receptors (red) are widely distributed
in the brain
CB2 receptors are presented in the peripheral immune cells
Molecular structure of CB1 and CB2 Receptors
• Inhibit adenylyl cyclase
• Activate mitogen-activated protein (MAP) kinase
• Inhibit voltage-gated Ca2+ channels
• Activate K+ channels
• Activate focal adhesion kinase
• Activate cytosolic phospholipase A2
• Activate (CB1R) or inhibit (CB2R) NO synthase
Signal Transduction of Cannabiods Receptors
Biological actions of Cannabioids
• Cortex, cerebellum and spinal cordBlock N-methyl-d-aspartate (NMDA) receptors, control tremor and spasticity.
• Basal ganglia, striatum and globus pallidusControl psychomotor disorders, interfer with dopamine transmission, inhibit GABA-mediated transmission, induce long-term depression, potentiate GABA-mediated catalepsy.
• Thalamus, hypothalamus and hippocampusControl pain initiation, wake–sleep cycles, thermogenesis, appetite and food intake, impair working memory, memory consolidation, inhibit glutamate-mediated transmission.
Endogenous Cannabinoid Ligands and Biological Activities
N-Arachidonylethanolamide (Anandamide, AEA)
2-Arachidonylglycerol (2-AG)
CB1 and CB2
Biosynthesis of Anandamide
Transport and degradation of Anandamide
Modulation of Degeneration and Inflammation in the CNS by the Endogenous Cannabinoids System
Zajicek J et al., Lancet 2003, 362:1517-26
Cannabinoid and MS: CAMS Trial
Baker D et al., Nature, 2000; 404: 84-87.
a, c: before b.d after 5 mg kg-1 i.p. with R(+)-WIN 55,212.e. Power spectra of hindlimb tremors
Cannabinoid receptor agonism inhibits tremor in autoimmune encephalomyelitis
Before
After
Spasticity Develops in Autoimmuno Encephalomyelitis
Control of spasticity by the cannabinoid system
Control
Control
SR141716A
SR141716A10 min
SR144528
R(+)WIN55212
Centonze, D. et al. Brain 2007 130:2543-2553; doi:10.1093/brain/awm160
Endocannabinoid levels in the CSF of control and MS subjects
Centonze, D. et al. Brain 2007 130:2543-2553; doi:10.1093/brain/awm160
Endocannabinoid metabolism in peripheral lymphocytes of control and MS subjects
Centonze, D. et al. Brain 2007 130:2543-2553; doi:10.1093/brain/awm160
Endocannabinoid metabolism in striatal and cortical slices of control and EAE mice
Centonze, D. et al. Brain 2007 130:2543-2553; doi:10.1093/brain/awm160
Effects of CB1 receptor stimulation on evoked glutamate-mediated EPSCs in corticostriatal slices of control and EAE mice
Centonze, D. et al. Brain 2007 130:2543-2553; doi:10.1093/brain/awm160
Effects of CB1 receptor stimulation on evoked GABA-mediated IPSCs in corticostriatal slices of control and EAE mice
Centonze, D. et al. Brain 2007 130:2543-2553; doi:10.1093/brain/awm160
Cannabinoid receptor binding in striatal and frontal cortical slices of control and EAE mice
Ortega-Guitierrez et al., FASEB J, 2005
UCM707 inhibits microglial activation and decreases the Microglial MHC class II antigen expression.
Spinal Cord Section5 mg/kg UCM, ip
Microglia/macrophages (CD11b+ cells)
Microglia/macrophages (tomato lectin binding)
Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD)
Effects of AMT Inhibitor on Microglial Activation and the Production of Inflammatory Cytokines
in TMEV-IDD MS model
Cannabidiol and Alzheimer's disease
• AD is the most common form of dementia in the elderly
• AD is characterized by the β-amyloid peptide (βA) within one of its pathological hallmark: the senile plaque. Activated microglia cluster at senile plaques, and this seems to be responsible for the ongoing inflammatory process in the disease.
B.G. Ramirez et al., J. Neurosci. 2005, 25: 1904–1913
Cannabinoid Receptor Localization in AD Brain
Frontal cortical
Nitration of CB1 and CB2 is increased in AD brain.
N-Tyr-immunoreactive astrocytes in control
Nuclear N-Tyr expression In control
Cytoplasmic N-TyrExpression in AD
Cannabinoid treatment prevents βA-induced Microglial activation in rats.
Tomato lectin binding – activated microglial in frontal Cortex, SCR or βA for 8 days
Cannabinoids prevent β-A-induced microglial activation in vitro
Cultured rat cortex microglial, Fibrillar βA
Effects of compounds acting on the elements of EC system in experimental models of AD
Compound Function Effects
Noladin CB1 agonist To counteract Aβ neurotoxicity
WIN55,212-2 CB1 and CB2 agonist To counteract Aβ-induced microglial activation
JWH-015 CB2 agonist To counteract Aβ-induced microglial activation
Rimonabant CB1 antagonist To counteract amnesia induced by Aβ peptides
Cannabidiol TRPV1 agonist >CB1 and CB2 To counteract Aβ-induced neuroinflamm. responses
VDM-11 EC reuptake inhibitor To counteract amnesia/neuro damage by Aβ peptides
Micale et al., Pharmacol. Res. 2007,56:382-392
The Involvement of the Endocannabinoid System in the Pathophysiology of AD
Cannabinoids and Amyotrophic lateral sclerosis
ALS: A fatal neurodegenerative disorder that selectively damages upper and lower motorneurons of the spinal cord, brainstem and motor cortex.
-- Glutamate excitotoxicity-- Mitochondrial dysfunction-- Oxidative stress-- Protein aggregation-- Proteosomal dysfunction-- Axonal transport deficits-- Cytoskeletal abnormalities -- Microglial activation-- Neuroinflammation and aberrant growth factor signaling
Levels of endocannabinoids in spinal cords of WT and symptomatic SOD1G93A mice.
L.G. Bilsland et al., FASEB J. 20 (2006):1003–1005.
Effect of treatment with WIN55,212–2 on the contractile characteristics of EDL muscles in SOD1G93A mice at 120 d of age
Extensor digitorum longus (EDL)
WT SOD1G93A WIN + SOD1G93A
Succinate dehydrogenase, an indicator of oxidative capacity
The neuroprotective effect of treatment with WIN55,212–2 in SOD1G93A mice
Spinal cord Section
Nissl statin
a: controlb: SOD1G93Ac: Win treated SOD
Motoneuron survival in SOD1.Faah –/– and SOD1.Cnr1 –/– mice.
(a) WT(b) SOD1G93A(c) SOD1.Faah –/–(d) SOD1.Cnr1 –/– mice.
The effect of Faah and CB1 receptor ablation on muscle force and motor unit survival in SOD1G93A
90 days of age
The potential neuroprotective mechanisms of cannabinoids in SOD1G93A mouse model of ALS.
• HD is an autosomal dominant, progressive neurodegenerative disorder
• Caused by a mutation in the IT15 gene of chromosome 4 coding for huntingtin (htt).
• Followed by an unstable expanded trinucleotide cytosine-adenine-guanine (CAG) repeat, which encodes for the amino acid glutamine.
• In HD, the gene has 40 and 60 CAG repeats leading to a mutant form of htt where glutamine is repeated dozens of times. The polyglutamines causes degeneration of medium spiny striato-efferent GABAergic neurons and atrophy of the caudate nucleus.
The Cannabinoid Pathway in Huntington’s Disease
The distribution of cannabinoid CB1 and dopamine D1 receptors in the SN of control and Huntington's disease Brain
SN: substantia nigra, autoradiograph
The binding of [3H]CP55,940 to CB1receptors in the caudate nucleus and putamen
Glass et al., Neuroscience, 2000, 97:505-519
The binding of [3H]SCH23390 to dopamine D1 receptors in the caudate nucleus and putamen
The binding of [3H]Raclopride to dopamine D2 receptors in the caudate nucleus and putamen
The binding of [3H]FNZ to GABAA receptors in the putamen and globus pallidus of the lenticular nucleus
CB1 Binding Capacity CB1 mRNA level
Wide-type Control
Transgenic HD
Lastres-Becker et al., 2002
Cannabinoid receptor stimulation depresses GABA transmission in WT but not in R6/2 HD mice
Effects of CB1 receptor stimulation on spontaneous glutamate-mediated EPSCs (sEPSCs) recorded from WT and R6/2 mice
Effects of compounds acting on the elements of EC system in experimental models of HD
Compound Function Effects
CP55940 CB1 & CB2 agonist Anti-hyperkinetic effects
Arvanil CB1 and TRPV1 agonist Anti-hyperkinetic effects
Cannabidiol antioxidant properties Neuroprotective and reverse GABAergic damage
Capsaicin TRPV1 agonist Anti-hyperkinetic, improvement DAergic and GABAergic system
AM404 EC reuptake inhibitor & TRPV1 agoonist Same as above
UCM707 EC reuptake inhibitor Anti-hyperkinetic effects
● PD -- degeneration of dopamine (DA)-containing neurons of the substantia nigra. The irreversible loss of the DA-mediated control of striatal function leads to the typical motor symptoms.
● Degeneration of dopamine neurons during experimental PD can be reduced by agonists of CB1, CB2, and non-CB1 or non-CB2 receptors – an effect that involves modulating the interactions between glial cells and neurons. CB1 receptors, however, also exert detrimental effects on dopamine cell survival by potentiating the toxic effects of the TRPV1 agonist capsaicin.
Cannabinoids and Parkinson's disease
Lastres-Becker et al Eur J Neurosci. 2001, 14:1827-32.
Cannabinoids reduce the frequency of glutamatergic sEPSCs in striatal spiny neurons of naïve and parkinsonian (6-OHDA) rats