Epilepsy1

M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

 Definition : - The chemical substance helpful for
signal transmission in central nervous system
&peripheral nervous system (via) the chemical
synapses is neurotransmitters.
 Synaptic transmission is the predominant means by
which neurons communicate with each other.

 The criteria for Chemical neurotransmitter
 1) found in presynaptic axon terminal.
 2) enzymes necessary for synthesis are present in
presynaptic neuron .
 3) stimulation under physiological conditions results
in release.
 4) mechanism exist for rapid termination of action.
 5) direct application to postsynaptic terminal mimics
the activation of nerve stimulus.

 6) drugs that modify metabolism of the
neurotransmitter should have predictable
physiological effects invivo assuming that the drug is
transported to the site where neurotransmitter acts.
 Not all neuron to neuron transmission is by
neurotransmitters , gap junctions provides direct
neuron to neuron electrical conduction.

 Neurotransmitter is stored in synaptic vesicle released
in response to nerve impulse & controled by calcium
influx.
 Release of neurotransmitter is quantal event , that is a
nerve impulse reaching presynaptic terminal result in
release of transmitter from a fixed number of synaptic
vesicle.
 Neurotransmitter action is terminated by metabolic
degradation , reuptake , or diffusion into other cell
types.

 Class :- 1 acetylcholine
 Class : -2 The biogenic amines
norepinephrine , epinephrine
dopamine , serotonin .
 Class : - 3 amino acids
gamma amino butyric acid (GABA) ,
glycine , glutamate , aspartate.
 Class : - 4 nitric acid (NO)
carbonmonoxide ( co )

 In addition to classical neurotransmitters many
neuropetides are identified as definite or probable
neurotransmitters,
eg : - substance p , neurotensin , enkephalin , β –
endorphin , histamine,
vasoactive intestinal polypeptide,
cholecystokinin , neuropeptide Y
& somatostatin.

 Neurotransmitters modulate the function of post
synaptic cells by binding to specific receptors of 2
types
 1) ionotropic receptors ( direct ion channels that open
after binding of neurotransmitters. )
2) metabotropic receptors ( interact with G proteins
stimulating production of second messengers &
activating protein kinases , which modulate the
cellular events. )

 G proteins couple several receptors to intra cellular
signaling system , linking neuronal excitability to
energy metabolism & second messenger systems.
 G protein binding receptors include adenosine , Ach (
muscarnic ), norepinephrine , dopamine , serotonin

 Kinetics of ionotropic receptors are fast , (< 1 ms ) ,
because neurotransmitters directly alter the electrical
property of the postsynaptic cell.
 Kinetics of metabotropic receptors functions over
longer time periods.
This contributes to the potential for selective & finely
modulated signaling by neurotransmitters

 The membrane of neuronal cell maintains an
asymmetry of inside outside voltage , & is electrically
excitable.
 Neuronal membranes are polarized to a potential of -
90 mV by the activity of Na+_k+ ATPase transport
system.

 Factors that control the neuroexcitability
1)voltage gated ion channels
2) neurotransmitter activated ion channels.
3)neuromodulators
4)second messenger system.
 The control of neuronal activity within normal limits
is by the modulation of excitatory & inhibotory events
simultaneously.

 Ligand gated channels are responsible for
communication between cells.
 Voltage gated sodium channels are involved in
propagation of action potential , rapid activation is at
-60mV due to opening of fast transient channels.
Voltage gated potassium channels contribute to
repolarization ,this regulate repeated firing of action
potential by prolonging after spike repolarization.

 Voltage dependent calcium channels trigger
neurotransmitter release , at rapid activation is around
-70mV.
 Autoantibodies to ca++ channels in motor nerve
terminal leads to decreased release of Ach from nerve
terminal , this is seen in eaton lambert myasthenic
syndrome.
 Voltage gated channels determine how inhibitory &
excitatory influences are integrated .

Acetyl choline
 Acetyl choline is the neurotransmitter used by all
motor axons that arise from spinal cord, that is at
neuromuscular junction.
 Junction consist of a single nerve terminal separated
from post synaptic region by synaptic cleft.
 Motor end plate is the specialized portion of the
muscle membrane involved in the junction.

 Junctional folds are prominent they contain high
density of Ach receptors.
 Synthesis of Ach takes place in cytosol of nerve
terminal .
choline acetyl transferase
acetyl coA+ choline Ach + coA
 Ach is incorporated into membrane bound particle
called synaptic vesicles.
 Assembly of synaptic vesicle with cell membrane
resembles assembly of transport vesicle involving
SNAREs.

 Release of Ach into synaptic cleft occurs by exocytosis ,
which involves fusion of vesicle with presynaptic
membrane.
 Nerve ending is depolarized by transmission of nerve
impulse this opens the voltage gated Ca++ channels ,
permitting influx of Ca++ from synaptic cleft to nerve
terminal , this Ca++ plays a role in exocytosis of Ach
vesicle.

 Approximately 200 vesicles are released into synaptic
space.
 Each vesicle contains 10000 molecules of Ach.
 Ach binds Ach receptor , receptor undergoes
conformational change opening the channel in the
receptor that allows entry of Na+, k+ resulting in
depolarization of muscle membrane.

 Properties of Ach receptor of NMJ :
nicotinic receptor (nicotine is an agonist for the
receptor)
a membrane glycoprotein containing 5 subunits. (
2αβγδ subunits).
only α subunit binds Ach with high affinity.
2 molecules of Ach binds receptor to open the ion
channel which permits Na+ , K+ the receptor is thus
transmitter gated ion channel.
autoantibodies to receptors are implicated in causation
of myasthenia gravis

 Snake venom α bungarotoxin binds tightly to the α
subunit & can used to label the receptor .
Formation of autoantibodies to Ach
receptors in NMJ
damage to receptors by autoantibodies
reduction in number of receptors
Episodic weekness of muscles supplied by cranial
nerves

 When the channel closes Ach dissociates & it is
hydrolyzed by acetyl choline esterase.
acetyl choline esterase
Ach + H2O Acetate +choline
 Choline is recycled into nerve terminal by active
transport , it can be used for synthesis of Ach.

 The classical neurotransmitter of autonomic ganglia
whether sympathetic or parasympathic is acetyl
choline.
 2 classes of receptors are present in autonomic nervous
system.
 1) nicotinic eceptors ,
 2) muscarnic recptors.
 Nicotinic receptors in autonomic ganglia are different
from those on skeletal muscle.

 Nicotinc & muscarnic receptors mediate excitatory
postsynaptic potentials (EPSP) , but these potential
have different time course.
 Stimulation of presynaptic neuron elicits a fast EPSP
followed by a slow EPSP.
 Fast EPSP results from activation of nicotinic receptors
which cause of ion channels to open.

 Slow EPSP is mediated by activation of muscarnic
receptors that inhibit the M current , a current that is
produced by K+ conductance.
 Besides acetyl choline sympathetic preganglion
neurons may release enkephalin , substance p , LHRH ,
neurotensin or somatostatin.

 Neurotransmitter in parasympathetic postganglionic
neurons is acetyl choline.
 Actions are mediated by 3 types of muscarnic
receptors.
 1) M1 receptor (neural ) produces slow excitation of
ganglia.
 2) M2 receptor (cardiac) activation slows the heart.
 3) M3 receptor (glandular) , causing secretion,
contraction of visceral smooth muscle , vascular
relaxation.

 Muscarnic Ach receptors act by way of inosine
triphosphate system & they may also inhibit adenyl
cyclase & thus decreasing cAMP synthesis.
 Muscarnic recptors also open or close ion channels
particularly K+ or Ca++ this action occurs through G
proteins.
 Muscarnic receptors relax smooth muscle by an effect
on endothelial cells which produces nitric oxide (NO) .

 Nitric oxide ( NO ) relaxes smooth muscles by
stimulating guanylate cyclase & there by increasing
levels of cGMP which in turn activates cGMP
dependent protein kinases.
 The number of muscarnic receptors are regulated &
exposure to muscarnic agonist decreases the number
of receptors by internalization of rceptor.

 The betz cells of motor cortex uses acetyl choline as
their neurotransmitter.
 Acetyl choline probably acts as an imporatant
neurotransmitter in basal ganglia which is involved in
control of movements.
 Deficits in cholinergic path way in the brain
implicated in some form of Alzheimer's disease.

 GABA major fast inhibitory neurotransmitter in the
fore brain. 30% synapses of C.N.S contain GABA.
 Glutamic acid dehydrogenase synthesizes
GABA from glutamate in nerve terminal .
 3 types of receptors GABA a
GABA b
GABA c

 GABA a & GABA c are ionotropic receptors & are post
synaptic linked to chloride channel.
 GABA b receptors are metabotropic may be pre or
post synaptic & are coupled to ca+ or k+ ion channels
via GTP proteins.
 Presynaptic GABA b receptors serve autoreceptors to
inhibit release from nerve terminal.

 Binding of GABA leads to an opening of chloride
channels & resultant hyperpolarization.
 Glycine is inhibitory neurotransmitter in brain stem &
spinal cord.
 Post synaptic receptor for glycine is ligand gated
chloride channel that allows influx of Cl- to
hyperpolarize the postsynaptic neuron

 Glutamate & aspartate are excitatory
neurotransmitters.
 Glutamate is responsible for 75% of excitatory
neurotransmission in brain.
 Synthesis of glutamate & aspartate within central
neuron & glial cells is from carbohydrates involved in
TCA cycle.

 Mitochondrial enzyme aspartate transaminase
interconverts glutamate & aspartate.
 Glia contains glutamine synthase which converts
glutamate to glutamine.
 Glutamine is subsequently transferred to neuron
where it is deaminated to glutamate by glutaminase.

 Glial inactivation & specific uptake systems for
glutamate reduces interstitial glutamate levels to
terminate neurotransmitter action & prevent
excitotoxic damage.
 Monosodium glutamate produces migrainous head
ache.
 Excessive glutamate can result in neurotoxicity ,
celldeath & neurodegeration seen alzheimer’s disease.

 The receptors are subdivided into 5 classes.
 1 )NMDA (N – methyl –D –aspartate )
 2 )AMPA (α amino 3 hydroxy 5 methyl 4 isoxazole
propionic acid )
 3 )The kainate recptor ( isolated from sea weed)
 4 )L –AP 4 ( synthetic agonist )
 5 )Metabotropic receptors.
 First four receptors are cation channels .

 Metebotropic receptors are linked to intracellular
production of diacylglycerol,& inositol triphosphate by
phosphoinositide path way.
 NMDA is receptor is complex contains 5 distinct sites
for binding
1 ) site for transmitter binding glutamate
2 ) a regulatory site that binds glycine.
3 ) a voltage dependent Mg++ binding site
4 ) a site that binds phencyclidine
5 ) a site that binds Zn++.

 NMDA receptor opens when glutamate binds & allows
influx of Ca++ & Na++ into the cell.
 Mg++ , zn++ , poly amines , & steroids can also
modulate NMDA.
 one of the most important controls on the ionic
conductance through the NMDA receptor is voltage
sensitive blocking by Mg++

 Activation of AMPA receptor channels may depolarize
the neuron sufficiently to remove the voltage
dependent Mg++ block & activate NMDA channels.
 AMPA & NMDA are co activated & are present on the
same part of the neuron.

 A separate site that modulates the gating of NMDA
channel binds polyamines such as spermine &
spermidine which are synthesized by neurons.different
concentration dependent effects have observed.
 Endogenous Zn reduces NMDA activated current.
 Zinc is present in high concentrations in the
hippocampus & released with some neurotransmitter
in nervous system.

 Hydrogen ions also modulate the ion conductance
which is maximal at slightly alkaline pH , & reduces
with increasing acidity.
 During hypoxic ischemic injury , progressive
acidification resulting from glycolytic metabolism ,
may turn off the NMDA receptor channel.

 AMPA receptor is coupled to both Na++ , & K ++
channels. it’s activation opens the above channels,
depolarizes the neuronal cell rapidly, it is responsible
for the majority of rapid excitatory neurotransmission.
 Kainate receptor is also coupled to Na++ , k++
channels.
 Kainate receptor has slower rate of depolarizing
capacity than AMPA receptor.

 Excitatory aminoacids are also able to interact with
metabotropic recptors that activate the second
messenger system, these receptors are found both pre
& post synaptically.
 Activation result in presynaptic inhibition & post
synaptic excitation.

 The spectrum of neurological disorders mediated by
excitotoxicity include epilepsy, stroke ,
neurodegerative disorders ( parkinson’s disease ,
amyotropic lateral sclerosis , AIDS dementia )
 Most strokes are caused by thromboembolic events
causing diminished perfusion resulting in reduction of
supply of oxygen & glucose.

 3 subsequent stages are there in the development of
brain damage caused by ischemia.
 1)induction ,
 2)amplification ,
 3)expression.
 Induction : ischemia causes depolarization of the
neuronal membrane leading to release of glutamate.

 Glutamate overexcites the NMDA receptors in adjacent
neuron , leading to abnormally large influxes of Ca++
& Na+ and resultant cell injury or death .
 In addition glutamate stimulate AMPA – kainate
receptor ( leading to additional influx of Na+ ) & also
metabotropic receptors , causing the release of ITP &
diacylgycerol.

 Amplification : further build up of intra cellular
calcium occurs by following mechanism ,
1) increased intracellular Na+ activates Na+ - Ca++
transporters.]
2)voltage gated Ca++ channels are activated by
depolarozation.
3) ITP release Ca++ into cytosol from within
endoplasmic reticulum.

 Expression : high levels of intra cellular Ca++ activates
Ca++ dependent nucleases , proteases , &
phospholipases.
Degradation of phospholipids
formation of platelet activating factor (PAF) &
release of arachidonic acid
eicosanoids (vasoconstriction)
damage by oxygen free radicals
This is called glutamate cascade.

 Huntington disease characterized by selective
neuronal death in corpus striatum & glial proliferation
.
 Apoptosis , protein aggregation , & excitotoxins may all
contribute cell death in huntington disease.
 Excitotoxicity is by glutamate cascade.

 The dopaminergic neurons are found in
nigrostrital , mesolimbic , mesocortical
tuberohypophysial systems.
 Dopamine synthesis occurs from tyrosine , tyrosine
hydroxylase is rate limiting enzyme in formation.

 Entry of dopamine into synaptic vesicle is is driven by
pH gradient established by a protein in vesicular
membrane that pumps protons into vesicle at the
expense of ATP
 Release of dopamine involves exocytosis.
 Dopamine has 5 post synaptic recptors
D 1 receptor family(D1 & D5)
D 2 receptor family(D2, D3, D4)
 D4 receptor exhibits 5 polymorphic variants.

 The effect of dopamine is to increase direct path way
by D 1 recptor, & supress indirect path way by D 2
receptor.
 D 1 receptor activation augments adenylate cyclase (
linked to stimulatory G protein).
 D 2 receptor activation decreases the activity of
adenylate cyclase ( linked to inhibitory G protein ).

 ATP dependent reuptake of dopamine achieved by a
high affinity transporter in presynatic membrane , this
is incorporated into vesicles & reused again.
 Degradation of dopamine occurs within synaptic cleft
or following reuptake ,within presynatic terminal.
 Mono amino oxidase B present in the outer membrane
of mitochondria & also in synaptic cleft.

 MAO –B & MAO – A are distinguished from each
other by preference for different substrates & by their
different susceptibility to various inhibitors.
 Both the above enzymes acts on dopamine to produce
3 – hydroxyphenyl acetaldehyde (DOPAC).
 DOPAC converted to homovanillic acid by the action
of catechol o methyl transferase.

 parkinson disease is due to loss of dopaminergic
activity & excessive cholinergic activity in basal
ganglia.
 Signs of parkinson disease reflects a deficiency of
dopamine in the substantia nigra , corpus striatum (
caudate nucleus & putamen )

 Basal ganglia are important for motor control they
include putamen
caudate nucleus
globus pallidum
substantia nigra
subthalamic nucleus .
 All circuits in basal ganglia are inhibitory utilizing
GABA except glutamatergic subthalamic input to
globus pallidum internum(GPi) which is excitatory.

 Cell damage in parkinson disease reflect a process of
ageing , 13 % of cells of substantia nigra are lost per
decade from 25 age onwards . ( parkinson disease
rarely occurs befor 40 years )
 Mutattions in gene encoding α synuclein , a
presynaptic protein involved in neuronal plasticity is
associated with parkinson disease.
 Lewy bodies are found strongly stained with
antibodies of α synuclein .

 Signs of parkinson disease appear when the level of
dopamine is droped in nigrosriatal system by 80%.
 Exposure to high levels of Manganese
( miners) leads to parkinson disease.
 Reserpine inhibit dopamine storage & many
neuroleptics block dopamine receptors.

 Schizophrenia is a manifestation of
hyperdopaminergia .
 Measurement of dopamine metabolite homovanillic
acid in CSF is high in schizophrenics.
 Level of D2 receptors appears to be increased in the
brains of schizophrenics.
 Dopamine mimetic drugs ( L dopa) induces
schizophrenia

 Low dopamine activity in prefrontal cortex of the brain
of schizophrenics correlate well with the negative
symptoms .
 Low dopamine activity in prefrontal cortex releases the
inhibitory action on subcortical dopamine neurons
resulting in elevated dopaminergic activity.

 Adrenergic neurotransmission is by norepinephrine &
epinephrine.
 The adrenergic neurons of locus ceruleus , pons , &
medulla project to every area of brain & spinal cord.
 Sympathetic postganglionic neurons typically release
norepinephrine.
 NE & E serve important role in the regulation of blood
volume & blood pressure.

 Norepinephrine is synthesized from tyrosine .
dopamine β hydroxylase
dopamine norepinephrine
cu
dopamine β hydroxylase is bound to inner membrane of
synaptic vesicle & release norepinephrine in a
tetrameric glycoprotein form.

 The overall system of epinephrine synthesis , storage &
secretion from adrenal medulla are regulated by
neuronal controls & also by glucocorticoid hormones
synthesized in & secreted from adrenal cortex in
response stress.
 Secretion of epinephrine is signaled by neural
response to stress , which is transmitted to adrenal
medulla by way of a preganglionic acetyl cholinergic
neuron.

 A small number of neurons in the medulla contain
phenyl ethenolamine –N- methyl tranferase enzyme
that converts norepinephrine to epinephrine with
SAM as methyl donor.
 These neurons project to the thalamus, brainstem ,
spinal cord.
 Concentration of epinephrine secreting terminals in
the paraventricular nucleus suggests a role in secreton
of oxytocin & vasopressin.

 Dense innervation of dorsal motor nucleus of vagus , &
nucleus solitarius suggets role in regulating
cardiovascular & respiratory reflexes.
 Receptors on target cells may be either α or β
adrenergic receptors.
 Receptors are further sub divided into α1, α2, β1 , β2 ,
β3.

 α1 receptor are located postsynaptically but α2
receptors may be either pre or postsynaptic .
 Receptors located presynaptically are autoreceptors
inhibit release of neurotransmitter.
 The effects of α1 receptors are mediated by activation
of ITP/ diacyl glycerol second messenger system.
 β receptors can be antagonized by action of α1
receptor.

 α2 receptors decease the rate of synthesis of cAMP
through an action on inhibitory G protein.
 β1&β2 receptors activates stimulatory G protein to
increase cellular cAMP levels.
 Activation of β receptor result in coactivation of β
adrenergic receptor kinase (BARK), this
phosphorylates the receptor.
 Phophorylation is prominent mechanism of receptor
desensitization.

 Number of β receptors is regulated .
 β receptor is phosphorylated & desensitized their
number also decreased if they become internalized.
 β receptors can also be increased by denervation.
 The number of α receptor is also regulated.

 β1 adrenergic receptors principally found in heart &
cerebral cortex.
 β2 receptors principally found in lung & cerebellum.
 β1 receptors equally prefer NE & E as agonist.
 β2 receptors prefer epinephrine to norepinephrine.

 In synaptic neurons norepinephrine decreases the
amplitude of calcium spikes.
 Excitatory effects of norepinephrine in various parts of
CNS & sympathetic ganglion neuron results from α1
receptor activation. This activity primarily depends on
blockade of a resting K+ conductance as a result
neuron depolarizes & firing rate increases.

 Inhibitory effects of norepinephrine results from α2
receptor activation , which results in increase of K+
conductance this hyperpolarizes the neuron &
decreases it’s firing rates.
 NE acting at α2 receptor also block Ca++ current.
 Both the above inhibitory mechanisms account for the
autoreceptor function of α2 receptors which decreases
neurotransmitter release.

 α1 adreno receptor activation results in ,
1)vasoconstriction ,
2) relaxation of gastrointestinal smooth muscle,
3) salivary secretion ,
4)hepatic glcogenolysis.

 α2 adreno receptor activation results in
1) inhibition of transmitter release, (including NE &
Ach from autonomic nerves)
2) platelet aggregation
3) contraction of vascular smooth muscle.
4) inhibition of insulin release.

 β1 adreno receptors activation results in
1) increased cardiac rate & force
 β2 adreno receptors activation results in 1)
bronchodilatation ,
2) vasodilation,
3) relaxation of visceral smooth muscle,
4) hepatic glycogenolysis,
5) muscle tremor.
 β3 adreno receptor activation results in lipolysis.

 The action of catecholamine neurotransmitters is
terminated by reuptake into presynaptic neuron by
specific transporters.
 Enzymes involved in metabolism are catechol 0
methyl transferase & monoamino oxidase .
 End product of norepinephrine & epinephrine
metabolism is 3 methoxy 4 hydroxy mandelic acid.

serotonin
 More than 95% of body’s serotonin is stored in
platelets & GI tract , only 5% is seen in brain.
 Serotonin is distributed in brain regions that affect
behaviour especially the hypothalamus & limbic
system.

 Availability of tryptophan is the main factor regulating
synthesis of tryptophan.
 Process of synthesis , storage , release , reuptake &
degradation are similar to catecholmines.
 Urinary 5 HIAA provides a measure of 5 –HT turn
over.

 Functions associated with 5-HT path ways
1)hallucination & behavioural changes,
2)sleep, wakefulness & mood ,
3) feeding behaviour,
4)control of sensory pathway including
nociception,
5) vomiting.
 Serotonin receptors are metabotropic.
 Melatonin a derived product of 5-HT has role in
establishing circadian rhythm.

 Histamine has neurotransmitter role in brain.
 Acts on metabotropic receptors.
 H1 receptors are excitatory & H2 , H3 receptors are
inhibitory.
 H1 receptors in cortex & RAS contributes to arousal &
wakefulness.
 Has role in food & water intake, thermoregulation

 Nitric oxide synthase is present in many CNS neurons.
 NO production is increased by mechanisms that raise
intracellular Ca++ concentration( eg: transmitter
action).
 NO affects neuronal functions by increasing cGMP
formation ,producing both inhibitory & excitatory
effects on neurons.

 ATP functions as neurotransmitter , it acts via
ionotropic receptors as fast excitatory transmitter , via
metabotropic receptors acts as neuro modulator.
 Adenosine exerts inhibitory effects through
metabotropic receptors.
 Neurons contain CO generating enzyme, heme
oxygenase , have role in cerebellum & olfactory
neurons which have cGMP sensitive ion channels.

Epilepsy1

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