EPILEPTOGENESIS AND DRUGS

Dr AKHIL AGRAWALMD Pharmacology(PG Resident)

BRIEF OUTLINE-1.DEFINITION2.HISTORY3.INDIVIDUAL EPILEPTOGENIC MECHANISM4.CAUSES OF EPILEPSY5. DRUG INDUCED EPILEPSY6.APPLICATIONS

An seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

A person is considered to have epilepsy if they meet any of the following conditions:(As per ILAE)

1. At least two unprovoked (or reflex) seizures occurring greater than 24 hours apart.

2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.

DEFINITIONS

Babylonians-presence of demons

Greeks and romans-curse of gods

Hippocrates offered epilepsy as a disease

Electrical hypothesis was discovered by hans berger when he invented the EEG

John Jackson (father of epilepsy)-“occasional sudden,excessive,rapid and local discharge of gray matter”

HISTORY

The process of the brain acquiring an initial insult and secondarily undergoing a series of epileptic events until the first observable seizure occurs.Sloviter & Bumanglag (2012) have proposed a secondary term “epileptic maturation” to describe the all encompassing processes that happen after epileptogenesis and that influence the secondary changes in the clinical phenotype.

EPILEPTOGENESIS

GABA GLUTAMATE CHOLINERGIC DOPAMINERGIC SEROTONERGIC NOR-ADRENERGIC

MAJOR PATHWAYS

It consists of mainly 2 receptors: GABA A

GABA B

GABA PATHWAY

Location of GABA A receptors-• Synaptic receptors -gamma

subunits(mostly post synaptic)• perisynaptic /extra synaptic -

deltas sub units responsible for phasic and tonic inhibition.

During status epileptics, there is increased neuronal hyper excitability and inhibitory GABAergic synaptic transmission becomes compromised

• Miniature inhibitory post-synaptic currents (mIPSCs) are reduced

• Number of active GABAA receptors per dentate granule cell is also decreased.

GABA A PATHWAY

Short term(during SE)• In vitro-large

decrease in GABA-gated chloride currents.

• In vivo-rapid reduction in the number of physiologically

active GABA receptors.

Changes in latency period-1.Minutes to hours – Activation of plasma

membrane receptors result in changes in the intracellular signal transduction pathways involved in the maintenance of vital cellular functions.

2. Hours to days- Long term changes in gene

expression result from the combined effects of repeated seizures, seizure-induced cell death, and subsequent neuronal reorganization

2 types of receptors: GABA B 1 GABA B2

Types: Slow - downstream

Ca2+/K+ channels upon binding with its endogenous ligand, GABA.

Long term- Ligand activation of GABAB receptors initiates G protein–dependent cell signaling pathways.

GABA B PATHWAY

Presynaptic receptors prevent neurotransmitter release

• Down-regulating the activity of voltage-sensitive Ca 2+-channels

• Direct inhibition of the release machinery.

Auto receptors inhibit the release of GABA, whereas hetero receptors inhibit the release of glutamate and several other neurotransmitters.

Postsynaptic receptors induce sIPSCs by activating Kir3-type K+-channels, which hyperpolarizes the membrane, favors voltage-sensitive  block of NMDA receptors and shunts excitatory currents

Dendritic receptors inhibit back propagating action potentials through activation of K+-channels.

GABA B PATHWAY

Two types of receptors:1.Ionotropic NMDA AMPA Kainate2.Metabotropic(8) Group1 Group2 Group3

GLUTAMATE PATHWAY

1.NMDA- An increase in glutamate excitatory transmission in the

hippocampus. Increase in the pool of ready-release glutamate at the mossy fiber-

pyramidal cell synapse in the CA3 as well as in DG. Number of NMDA receptors present in neuronal cell membranes

appears to increase.2.AMPA:• Ca2+ influx into neurons causing excitotoxicity and cell death.• Synaptic changes due to alterations in second messenger signaling

Mechanism of action

3.KAINATE: Causes slow EPSP’s to promote epileptogenesis.4. METABOTROPIC RECEPTORS: Group I- epileptogenic in nature when bound by glutamate. Group II- promote antiepileptogenic effects when bound by

glutamate5.Several morphological changes in the hippocampus occur during epileptogenesis associated with glutamate dysregulation: Hippocampal sclerosis, shrinkage, and reactive gliosis Neuronal loss in hilar mossy cells, interneurons, and pyramidal

neurons of the CA3 and CA1 are also observed in the granule cell layer

Receptor Mechanism of action

NMDA Glutamate and Glycine mediated

AMPA Influx of Na+,Ca+ and efflux of K+

KAINATE Slow EPSP’s

Group I(1,5) Phospholipase C (PLPC), protein kinase C (PKC)

Group II(2,3) Inhibits c-amp formation, directly activates K+ channels and inhibits voltage sensitiveCa2+ channels

Group III(4,6,7,8) Inhibits neuro-transmitter release

Promote epileptogenesis such as a decrease in GABAergic interneurons (which could cause an in increase in glutamate neurotransmission)

A decrease in membrane expressed GABAB receptors (which could also cause an increase in glutamate neurotransmission)

NMDA PATHWAY AFFECT BY GABA

Ach causes increased seizure activity by acting on following brain parts:

Piriform cortex>amydala>hippocampus> thalamus >cortical areas &striatum

Specific areas:Piriform cortex-(substantia nigra & area tempestas)

CHOLINERGIC PATHWAY

MECHANISM- Cytotoxic activity seen in hippocampus and

cortical neurons Disruption of polymerization of microtubules Altered sensitivity to glutamate

excitotoxicity Decrease in expression of synaptic proteins. Area tempestas-hyperactivity in

hippocampus Direct cholinergic input/indirect to ento-

rhinal cortex.

DOPAMINERGIC PATHWAYDopamine receptors

Location in brain

D1 CP, nucleus accumbens , substantia nigra

D2 CP, nac, SN pars compacta

D3 Limbic systemD4 Frontal cortex,

amygdala, SN, hippocampus

D5 Entorhinal cortex, SNR, and hippocampus (dentate gyrus)

DOPAMINERGIC PATHWAYReceptor Action

D1 type(D1,D5)(PRO-CONVULSANT)

increases cAMP levels and protein kinase A (PKA) activity via the stimulation of adenylyl cyclase (AC)

D2 type(ANTI-CONVULSANT)(D2,D3,D4)

inhibit AC activity,antogonises D1 action(c-amp dependent)

Activation of glycogen synthase kinase 3β(c-amp independent)

Serotonin has a protective mechanism against epilepsy.

Main mechanism: Hyperpolarization of

glutamatergic neurons by 5-HT1A receptors(K+ conductance)

Depolarization of GABAergic neurons by 5-HT2C receptors.

SEROTONERGIC PATHWAY

5HT1 receptors

5 HT 2C Receptors

Considered to have protective role in epilepsy.

Highest affinity for a2

adrenergic receptors. Established role in the

control of limbic seizures by increasing noradrenaline levels in structures that are critically involved in the generation of limbic seizures, such as the hippocampus.

NOR-ADRENERGIC PATHWAY

VASCULAR METABOLIC INFECTION DRUGS AND COMPOUNDS AUTOIMMUNE SYSTEMIC DISEASES GENETIC

PATHOPHYSIOLOGIC MECHANISMS PRODUCING SEIZURES

Cerebro-vascular accident(stroke) Congenital vascular

malformation(cavernous)

VASCULAR CAUSES

METABOLIC CAUSESToxin Mechanism

Increased excitationPyrethrumOrganophosphateAmanita

Na channelCholinergic excitationGlutaminergic stimulation

Decreased inhibitionStrychnineBicuculine

GABA antagonismGlutamate antagonism

Cyanide Interference with energy metabolism

Lead Unknown cause

Metabolic conditions associated with seizures:

1.Alkalosis 2. Hyponatremia3. Hypoglycemia 4. Hypocalcemia/hypercalcemia5. Hypoxemia 6. Hepatic/Renal failure 7. Hyper osmolality (hypernatremia, nonketotic hyperosmolar diabetes mellictus) Inborn errors of metabolism:• Errors in carbohydrate

metabolism(galactosemia)• Urea cycle enzyme deficiency

Virus(HSV.measles,rubella) Bacteria(H. influenzae, N. meningitidis) Fungal( C. neoformans, C. immitis, H.

capsulatum, C. albicans) Protozoal (Plasmodium ,Toxoplasma ) Helminthic (taenia solium, Echinoccocus

granulosis)

INFECTIVE CAUSES

Various Diseases:1. SLE2. Sjögren’s

Syndrome3. Wegener’s

Granulomatosis4. Sarcoidosis5. Celiac Disease

Mechanism: Vascular disease • Platelet-fibrin thrombi

(e.g., TTP)• Prothrombotic state• Anticardiolipin antibody• Emboli Vasculitis Antineuronal antibodies Immune complexes Cytokines

AUTO-IMMUNE CAUSE

Various mechanism seen are: A particular body system has been

sufficiently impaired to produce a lowering of the seizure threshold and the induction of “reactive seizures.

A state of cortical neuronal instability, such as a (stroke with infarction, hemorrhage, embolus)

Encephalopathy

SYSTEMIC CAUSE

GENETIC CAUSE

Study of inheritance of heritable changes in gene expression that occur with no modifications to the DNA sequence.

Different types: DNA methylation histone modification action of non-coding RNA

EPIGENETICS AND EPILEPSY

DNA methylation

Histone modification

Action of non-coding RNA

Various mechanism of action are: Cerebral receptors Electrolytic disturbance Brain edema(vasogenic& cytotoxic) Metabolic effects Posterior reversible leukoencephalopathy

syndrome

DRUG INDUCED EPILEPSY

Drug MechanismAnti-infective  Peniciilin and related drugs Inhibits GABA binding to GABAA receptor(allosteric

modulation)Blocks GABAA chloride channel

Fluoroquinolones Inhibit GABA binding to GABAA receptorIsoniazid Inhibits pyridoxine kinase, resulting in decreased

GABA synthesis(formation of IPH)

Bromocriptine,pergolide Blocks dopaminergic transmissionMetronidazole Leads to accumulation of hydroxy- and 1-acetic

acid metaboliteTCA Inhibition of serotonin uptake in the cleftPhenothiazine Dopamine blocking propertyMOA –A inhibitor Produces serotergic activation(alpha-motor

neuron excitability)Selective serotonin reuptakeInhibitor

Decreases GABA transmission in the hippocampus

Phenothiazines Antagonizes postsynaptic, mesolimbic dopamine receptors in the brain

CEREBRAL RECEPTORS

Local anesthetics Antagonizes Na1 channelsMeperidine Leads to accumulation of normeperidine

metaboliteTramadol Inhibits monoamine uptakeTheophylline Antagonizes anticonvulsant effects of brain

adenosineCalcineurin Down regulates GABAA receptor activationBrain-stem stimulantsPentetrazolPicro-toxin

GABA excitation and inhibits GABA inhibition respectively

Spinal stimulantsstrychnine

Blocks inhibitory action of glycine at post synaptic receptor

General anesthesiaEnfluraneetomidate

Increased excitability in limbic systemDisinhibit ion of sub-cortical activity

Local anaesthesia+epinephrine Ischemia in spinal cord(transient epilepsy)Radio contrast dye(gadolinium) Direct action on cerebral cortex

Electrolyte disturbance Drugs

Hypo-natremia Vincristine,vinblastine,cyclophosphamide

hypokalemia Theophylline

ELECTROLYTE DISTURBANCES

Drugs Mechanism

Metronidazole Vasogenic edema

IVIg

An intramyelinic edema in the myelin sheathCytotoxic edema

VASOGENIC AND CYTOTOXIC EDEMA

Drug Mechanism

Salicyclate High anion gap metabolic acidosis

Malnutrition Inhibits glucoronidation(valproate)

METABOLIC EFFECTS

The PRES has been described after the intake of immunosuppressants such as tacrolimus, Cyclosporine.

It is characterized by capillary-leak syndrome in the brain caused by changes affecting the vascular endothelium.

Clinical symptoms are headache, vomiting, confusion, seizures, cortical blindness and other visual symptoms.

Posterior reversible leukoencephalopathy syndrome

Drug EffectVariant methionine synthetase, modified effect of methotrexateOn homocysteine metabolism

Methotrexate encephalopathy

Human thymidylate synthetase gene

5- fluorouracil-associated hyperammonemic encephalopathy

DRUGS PROMOTING GENETIC SUSCEPTIBILITY

Benzodiazepine- in association with LENNOX GASTAUT Syndrome or WEST Syndrome

Valproate/carbamazepine induced encephalopathy(accumulation of CBZ epoxide) esp. in children

Vigabatrin-increased GABA in brain

Anti-epileptic drug induced seizure

NOVEL TARGETS FOR EPILEPTOGENESIS

Use in animal experimental model PENICILLIN MODEL PENTYLENTETRAZOL MODEL BICUCULLINE MODEL KAINIC ACID MODEL

Application of epileptogenic drug

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References

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