neha final seminar

8/13/2019 Neha Final Seminar

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Neurotoxicity:

Excitotoxicity

ByNeha P


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First observed in 1954 by T. Hayashi, a

Japanese scientist who noted that direct

application of glutamate to the CNS

caused seizureactivity, though this report

went unnoticed for several years.

Historical Events
http://en.wikipedia.org/w/index.php?title=T._Hayashi&action=edit&redlink=1http://en.wikipedia.org/wiki/Seizurehttp://en.wikipedia.org/wiki/Seizurehttp://en.wikipedia.org/w/index.php?title=T._Hayashi&action=edit&redlink=1


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INTRODUCTION


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Central Nervous

System (CNS) Brain & Spinal Cord

Peripheral Nervous

System (PNS) Afferent (sensory)

NervesCarry sensoryinformation to the CNS

Efferent (motor)

NervesTransmit informationto muscles or glands


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Cells of the Nervous

SystemNeurons Signal integration/generation;

Supporting Cells (Glia cells) Astrocytes (CNS blood brain

barrier)

Oligodendrocytes (CNS

myelination)

Schwann cells (PNS myelination)

Microglia (activated astrocytes)


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Neurons are post-mitotic cells

High dependence on oxygen

Little anaerobic capacity

Brief hypoxia/anoxia-neuron cell death

Dependence on glucose

Sole energy source (no glycolysis)

Brief disruption of blood flow-cell death

High metabolic rate

Many substances go directly to the brain via

inhalation

Why is the Brain ParticularlyVulnerable to Injury?


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Blood Supply to the Brain


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Blood-brain Barrier Anatomical Characteristics

Capillary endothelial cells aretightly joined no pores betweencells

Capillaries in CNS surrounded byastrocytes

Active ATP-dependenttransportermoves chemicalsinto the blood

Not an absolute barrier Caffeine (small), nicotine Methylmercury cysteine

complex Lipids (barbiturate drugs and

alcohol)

Susceptible to various damages


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BBB can be broken down by:

Hypertension: high blood pressure

opens the BBB

Hyperosmolarity: high concentration

of solutes can open the BBB. Infection: exposure to infectious

agents can open the BBB.

Trauma, Ischemia, Inflammation,

Pressure: injury to the brain can open

the BBB.

Development: the BBB is not fully

formed at birth.


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Why Glutamate Receptors are

Important in Neurology:

Glutamate is present in millimolar quantities inmost cells, including neurons and glia

Glutamate is the main excitatoryneurotransmitter in the mammalian CNS

Glutamate is released in large quantities during

StrokeTraumaEpilepsyPossibly in chronic neurological disorders


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Excess glutamate is released at the synapsethrough

Synaptic activity

Reverse operation of glutamate transporters

Reduced re-uptake (due to reduced ATPlevels)

Glutamate levels may rise at the synapse tohundreds of micromolar, which is enough to causeexcitotoxicity.

Why Glutamate Receptors are

Important in Neurology:


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What happens to neurons with excess

glutamate?

Normal Neuron


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What happens to neurons with excess

glutamate?

Cell SwellingDendritic

BeadingAxons: nochange

Glutamate


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Excess glutamate kills neurons through Ca2+overload


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Calcium Homeostasis

Ca ions are ubiquitous intracellular 2ndmessengersresponsible for a multitude of cellular functionsincluding

Activation of numerous enzymes responsible for

Gene expression

Protein structure

Metabolic functions

The control of differentiation, polarity,synaptogenesis

Synaptic efficacyneuronal function & activity


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Calcium HomeostasisFor these reasons cells maintaina very tight control of Ca ions

[Ca2+]I: [Ca2+ ] e is 1 :

20,000

Ca2+ ions are sequesteredinto intracellular organelles

Ca2+ ions are activelypumped in and out of

cellular compartments

Cells contain diverse Ca2+

buffering molecules torestrict the diffusion of Ca2+

ions.


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Calcium Neurotoxicity

Ca2+ Excess is felt to be deleterious toneurons.

How much is too much remainscontroversial.

It is likely that Ca2+ ions activate distinct 2ndmessenger signaling pathways in neurons

that cause them to die.

Excitotoxicity causes Ca2+ Excess.


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Scheme Leading to Ca Excess:

The Case of Neurons


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Scheme Leading to Ca Excess:

The case of axons (white matter)


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Neurotoxic Phenomena triggered

by Calcium Excess

The formation of free radical species

Nitric Oxide formation

Calcium Activated Proteases

Endonucleases, Apoptosis, Necrosis

Mitochondrial Damage

Acidosis


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Free radicals Free radicals are reactive oxygen species

having a single unpaired electron:

e.g.: Superoxide (O2-), hydroxyl (OH-)

Free radicals produce damage by reacting(oxidizing) with critical cellular elements,usually structural proteins, membrane

lipids, DNA. Free radicals are produced mostly in

mitochondria.


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Mitochondrial e- transport


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Superoxide production:

Although molecular oxygen is reduced to water in

the terminal complex IV by a sequential four-electron transfer, a minor proportion can bereduced by a 1e addition that occurs predominantlyin complex III but also in complex I.

A chance exists that this second electron can betransferred to molecular oxygen, generating thesuperoxide anion O2.

Thus- normal mitochondria produce a small amountof superoxide.This superoxide isnormally scavengedby superoxidedismutase (SOD)


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Excitotoxicity and ROS:

Calcium loading of isolated mitochondriaincreases the production of O2

Excitotoxicity causes mitochondrial Ca

loading.

INSID

E OUTS

IDE

Mitochondria

O-.

2 O-.

2 H O

2 2

SOD Fe2+OH.

H O2

catala

se

[Ca ]2+

MnTBAP

Ca2+

Ca2+


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Mitochondrial membrane potential upon NMDA exposure


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Nitric Oxide Production

NO is a gaswith a half-life of 6s.

It is produced in:

- Vascular endothelium (vasorelaxant)

- Glial cells

- NeuronsIt is considered by many to be a neurotransmitterassociated with processes related to synapticplasticity, learning and memory.


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NO toxicity:

NO is a relatively innocuous gas.

However, when combined withsuperoxide:

NO + O2-= ONOO-

ONOO-is a highly reactive free radicalspecies that produces damage inneurons.


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Nitric Oxide & free radical

Production

IN

SIDE OU

TSIDE

MitochondriaO-

.2 O-

.2 H O2 2

SOD Fe2+OH.

H O2

c

atala

se

NO

NOS

Ca -CaM2+

OONO -

[Ca ]2+PLA2

Arachidonic acid COX

ROS

Ca2+

Ca2+


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Calcium activated proteases

( MAP2 immunofluorescence images )

Controls NMDA Recovery


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Calcium-activated proteases

Calcium-dependent proteolysis contributes to recovery of dendriticstructure after NMDA exposure. Calpain activation is not necessarilydetrimental and may play a role in dendritic remodeling after neuronal

injury.

No

Calpain

Inhibitor

C

alpain

Inhib

itor

E d l t i


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Endonucleases, apoptosis,

necrosis

Necrosis: Acute cell death characterized by cell &organelle swelling. Is generally rapid, and occursdue to massive insults.

Apoptosis: Slower cell death, characterized by cell

shrinkage, nuclear fragmentation, and may bemediated by a death sequence dictated by agenetic program.


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Endonucleases, apoptosis,

necrosis

Endonucleases are thought to be

calcium-activated enzymes thatcleave DNA

May be responsible in triggeringapoptosis.


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REFERENCES Eric J, Nelson, Jon Connolly , Patrick McArthur,

2002 . Nitric oxide and S-nitrosylation : excitotoxicand cell signaling mechanism . Biology of the

Cellvol. 95 issue 1 January, 2003. p. 3-8.

Doble ,A ,1999.The role of excitotoxicity inneurodegenerative disease: implications for

therapy. Pharmacol Ther. 1999 Mar;81(3):163-

221. M, FLINT BEAL, 1992. Mechanisms of

excitotoxicity in neurologic diseases. The FASEB

Journalvol. 6 no. 15 3338-3344.


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Almeida, A., Bolaos, J.P., 2001. A transient inhibition ofmitochondrial ATP synthesis by nitric oxide synthase

activation triggered apoptosis in primary cortical neurons.

J. Neurochem. 77, 676690.

Snyder, S.H., 1992. Nitric oxide: firstin a new class ofneurotransmitters? Science 257, 494496.

Urushitani, M., Nakamizo, T., Inoue, R., Sawada, H.,

Kihara, T.,Honda, K., et al., 2001. N-methyl-D-aspartate

receptor-mediated mitochondrial Ca2+ overload in acuteexcitotoxic motor neuron death: a mechanism distinct from

chronic neurotoxicity after Ca influx. J. Neurosci. Res. 63,

377387.2+

REFERENCES

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