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4/8/13 1 April 3, 2013 Nervous System Disease and Neuron Excitability MSG and Glutamate Excitotoxicity Excitotoxicity implicated in: Stroke Huntington’s Disease Neuropathic pain Drug dependency Ryan and Mary Beth Dravet's Syndrome Symptoms : Severe myoclonic eplisepsy in infancy (SMEI), polymorphic epilepsy in infancy (PMEI), epilepsy with polymorphic seizures Treatments : Daily Anticonvulsant Medication (ex. clobazam, clonazepam, leviteracetam), Alternative Treatments (Intravenous Immunoglobin Therapy, Vagus Nerve Stimulation, ketogenic diet) Why Interesting? Most often caused by a mutation in a gene that encodes a sodium ion channel in the brain Diana and Brian Cocaine Addiction Short-term symptoms: – Euphoria/anxiety Energy/mentally alert Increased sympathetic responses (HR, BP, T) Muscle twitches Heart attack, seizure, sudden death Long-term symptoms: – Craving Increased tolerance Increased irritability Paranoid psychosis Treatment: – Detoxification Behavioral Therapy Medication: – Modafinil – N-acetylcysteine Hypothesis: Dopaminergic input from ventral tegmental area nucleus accumbens Increase dopamine levels by blocking dopamine transporter protein Yoshi and Andy

Cocaine Addiction - Cornell University...Drug:! • Zarontin (ethosuximide)! • Prevents absence seizures! • Although debated, commonly believed to be T-type channel blocker! Characteristic

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Page 1: Cocaine Addiction - Cornell University...Drug:! • Zarontin (ethosuximide)! • Prevents absence seizures! • Although debated, commonly believed to be T-type channel blocker! Characteristic

4/8/13

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April 3, 2013 Nervous System Disease and Neuron Excitability

MSG and Glutamate Excitotoxicity

Excitotoxicity implicated in: •  Stroke •  Huntington’s Disease •  Neuropathic pain •  Drug dependency

Ryan and Mary Beth

Dravet's Syndrome

Symptoms: Severe myoclonic eplisepsy in infancy (SMEI), polymorphic epilepsy in infancy (PMEI), epilepsy with polymorphic seizures

Treatments: Daily Anticonvulsant Medication (ex. clobazam, clonazepam, leviteracetam), Alternative Treatments (Intravenous Immunoglobin Therapy, Vagus Nerve Stimulation, ketogenic diet)

Why Interesting? Most often caused by a mutation in a gene that encodes a sodium ion channel in the brain

Diana and Brian Cocaine Addiction

•  Short-term symptoms: –  Euphoria/anxiety –  Energy/mentally alert –  Increased sympathetic

responses (HR, BP, T) –  Muscle twitches –  Heart attack, seizure,

sudden death •  Long-term symptoms:

–  Craving –  Increased tolerance –  Increased irritability –  Paranoid psychosis

•  Treatment: –  Detoxification –  Behavioral Therapy

•  Medication: –  Modafinil –  N-acetylcysteine

•  Hypothesis: –  Dopaminergic input from

ventral tegmental area nucleus accumbens

–  Increase dopamine levels by blocking dopamine transporter protein

Yoshi and Andy

Page 2: Cocaine Addiction - Cornell University...Drug:! • Zarontin (ethosuximide)! • Prevents absence seizures! • Although debated, commonly believed to be T-type channel blocker! Characteristic

4/8/13

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•  Most common Motor Neuron Disease (MND)

•  Progressive degeneration of one or more of the following:

–  Corticospinal tracts –  Anterior horn cells –  Bulbar motor nuclei

(brainstem, cranial nerves)

http://wc1.smartdraw.com/examples/content/examples/10_healthcare/anatomy_illustrations/efferent_lateral_corticospinal_tract_of_the_nervous_system_l.jpg

•  Common Symptoms (early late)

– C

•  Treatment/Prognosis –  No cramps, weakness, muscle atrophy

of hands or feet, spreading up limbs –  Clumsiness, spasticity –  Fatigue –  Difficulty controlling tongue

movements (impaired speech)/facial expression

–  Inappropriate affect (involuntary laughing or crying)

–  Death by asphyxiation (failure of respiratory musculature)

–  ure –  Drugs for symptom management

(spasticity, cramps, inappropriate affect) –  Home care

All textual information from www.merckmanuals.com http://phillysportshistory.com/wp-content/uploads/2011/06/lou_2.jpg

Amyotrophic Lateral Sclerosis ���“Lou Gehrig’s Disease”

Paul

Amyotrophic Lateral Sclerosis (ALS)

•  Idiopathic fatal motor neuron disease affecting voluntary muscle movements

•  Symptoms: signs of both upper and lower motor neuron damage –  UMN damage: stiff muscles, exaggerated reflexes –  LMN damage: muscle weakness and atrophy, muscle cramps, fasciculation

(twitches) –  Late symptoms: inability to walk, move limbs, swallow, chew, or breathe

•  Possible Causes: –  Excess glutamate in the spinal fluid and serum glutamate-induced excitotoxicity

incites neurodegeneration through activation of calcium-dependent enzymatic pathways. •  Free radicals generation, which can cause damage to intracellular organelles. •  SOD1 mutation

•  Treatments: –  None, to undo motor neuron damage, just prevent further damage –  Riluzole (Rilutek) – decreases glutamate release to avoid further motor neuron damage

Tiffany and Tracy

Amyotrophic Lateral Sclerosis(ALS)

•  =Lou Gehrig’s disease •  Motor Neuron Diseases •  Syndromes :

–  Rapidly progressive weakness, muscle atrophy, fasciculation, muscle spasticity, difficulty speaking, difficult swallowing, difficulty breathing.

•  Causes : –  hereditary (chromosome 21), mutation of SOD1

•  Pathophysiology: –  Death of both upper and lower motor neurons in motor

cortex of brain

Hench Wu and Yi-Yun Ho Copyright © 2012 Stem Cell Treatment Solutions Pty Ltd.

Page 3: Cocaine Addiction - Cornell University...Drug:! • Zarontin (ethosuximide)! • Prevents absence seizures! • Although debated, commonly believed to be T-type channel blocker! Characteristic

4/8/13

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Autosomal Dominant Nocturnal Frontal Lobe Epilepsy(ADNFLE)

•  Epileptic disorder characterized by violent seizures during sleep

•  Usually begins in childhood, decreasing in severity with age

•  Mutations of nicotinic ACh receptors – CHRNA4 – CHRNB2 – CHRNA2

•  Treated by anti-epileptic drugs, vagal nerve stimulation

ghr.nlm.nih.gov, 2009; Kurahashi and Hirose 2002

Joel and Ben

Multiple sclerosis, a demyelinating disease

•  Autoimmune disorder that affects multiple parts of the CNS.

•  The myelin sheath is damaged by an auto-inflammatory reaction provoking demyelination.

•  Affects signal transduction. •  Degenerative. •  Many symptoms, the most common are:

–  Decrease in sensitivity (fingers, toes). –  Lost of mobility.

•  No cure but some drugs can reduce the reactivity of the immune system.

•  Mainly affects females under 30. Source: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001747/

Andrea

Parkinson’s Disease •  Symptoms

–  Tremor –  Bradykinesia –  impaired posture

•  Cause –  degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) results in

dopamine (DA) imbalance –  DA imbalance causes reduced excitation of striatum and eventually motor cortex –  Reduced activity of motor cortex causes the symptoms of Parkinson’s Disease

•  Treatment –  Dopamine supplement

•  L-DOPA, a dopamine precurosor –  Dopamine agnoist

•  Activate Dopamine receptors –  Deep brain stimulation

•  Uses a pacemaker-like device to deliver periodic shocks to select parts of the brain •  The shocks reduce symptoms of Parkinson’s Disease such as tremors

Source: http://www.dana.org/news/brainwork/detail.aspx?id=800

Woo and Yichi Diabetic Neuropathy •  A progressive neurodegenerative disease that causes denervation

of axon by eating away at the myelin sheath. •  Diabetic neuropathy is a negative response to hyperglycemia •  Denervation causes a “cross-talking” between nerves that causes

an increase in sodium channels at site of denervation •  Increase in sodium channels creates Long Term Potentiation that

causes a burst of electrical stimulation, called Hyperexcitability, into the dorsal horn in the Central Nervous System

•  Hyperexcitability causes a release of Glutamate at the synaptic junction in the dorsal horn causes neuronal depolarization which increases signaling to the brain that registers the increase in dorsal horn signaling as pain

Norm

Page 4: Cocaine Addiction - Cornell University...Drug:! • Zarontin (ethosuximide)! • Prevents absence seizures! • Although debated, commonly believed to be T-type channel blocker! Characteristic

4/8/13

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Childhood Absence Epilepsy Symptoms: •  onset 4-10 yrs, peak 5-7yrs •  short lasting (∼10 s) seizures

•  sudden impairment of consciousness •  interruption of ongoing activity •  upward blank stare

���Prognosis: most patients “grow out” of it Hypothesized Cause: •  genetic mutations alter T-type calcium

channel properties (e.g., lower voltage activation) •  found often in thalamus •  open near resting potential •  create low-threshold spikes after EPSPs •  depolarize beyond threshold for ���

Na-dependent APs   Hyperexcitable T-type channels   inappropriate oscillations in thalamus   seizures

Drug: •  Zarontin (ethosuximide)

•  Prevents absence seizures •  Although debated, commonly

believed to be T-type channel blocker

Characteristic 3Hz spikes

Mark and Dinan

Neuromyotonia •  Description – peripheral nerve hyperexcitability causes

spontaneous muscular activity and may cause excessive stiffness and twitching

•  Mechanism – cause is still not 100% understood; one prominent explanation suggests an autoimmune origin for the disease; it is believed that certain antibodies bind to the potassium channels in peripheral nerves resulting in continuous hyperexcitability

John and Andrew