EPILEPSY

Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, and nearly two out of every three new cases are discovered in developing countries. Epilepsy is more likely to occur in young children, or people over the age of 65 years; however, it can occur at any time. As a consequence of brain surgery, epileptic seizures may occur in recovering patients.

SEIZURE CLASSIFICATION
‡ PARTIAL SEIZURES
I. II. SIMPLE(CONCIOUS NOT IMPAIRED) COMPLEX PARTIAL SEIZURES(PSHYCOMOTOR SEIZURES) PARTIAL SEIZURES EVOLVING TO SECONDARY GENERALIZED CONVULSION

‡ GENERALIZED SEIZURES
I. II. III. IV. V. VI. ABSENCE SEIZURES MYCLONIC CLONIC TONIC TONIC-CLONIC ATONIC

III.

PARTIAL SEIZURES:
‡ Initially neuron discharge originates from specific limited cortical area known as FOCUS. ‡ They response fairly well to antiseizure drugs.
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ SIMPLE PARTIAL SEZUIRE: ConSciousness Temporal lobe seizure-pshycotic symptoms Parietal lobe seizure-sensation,tingling,numbness,pain COMPLEX PARTIAL SEIZURES: Unconsciousness Staring Inability to response

PARTIAL SEIZURES EVOLVING TO SECONDARILY GENERALIZED SEIZURES:
.Abnormal electrical activity .Evolving into a secondary generalized tonic-clonic seizure .Diagnosis is difficult

GENERALIZED SEIZURES:
‡ ‡ ‡ ‡ Generalized from the outset Envolvement of both cerebral hemisphere Loss of conciousness Initial removal discharge spreads quickly to entire gray matter

1.ABSENCE SEZUIRES TYPICAL :
‡ ‡ ‡ ‡ Loss of consciousness Rapid onset and cessation of seizures Absence begins with the a change in facial expression,followed by a period of motionless,blank staring No memory of events during seizures

ATYPICAL: ‡ Slower onset and cessation ‡ Last longer ‡ Clonic motions,automatism or autonomic symptoms ‡ Response well to AEDs 2.MYOCLONIC
‡ ‡ ‡ ‡ Sudden, very brief jerking contractions Contraction may effect individual muscles Occurs in all age groups Symptoms ranging from tremors to falling down

3.TONIC

‡ ‡ ‡ ‡

Mostly occurs in children Characterized by increased tone in extension muscles Duration of contraction is longer Vocalization occurs as result of contraction of thoracic muscles

4.ATONIC SEIZURES
‡ ‡ ‡ ‡ ‡ Sudden decrease in muscle tone Head drop , drooping of limbs , loss of all muscle tone , resulting in falling down Drop attacks Common in children Control over this type of seizure is difficult

5.CLONIC SEIZURES
‡ Always occurs in babies

‡ ‡

Loss of consciousness occurs stimultaneouslu Asymmetric jerking motions

6.TONIC-CLONIC SEIZURES
‡ ‡ ‡ ‡ ‡ Represents a maximum epileptic response of brain Absence of an aura Tonic stiffness of all muscle groups Initial contraction,rapidly followed by prolonged extension Loss of bladder control, biting of tongue or inside of mouth

MECHANISM OF ACTION FOR THE ANTISEIZURE DRUG:
‡ ‡ Seizures results from brusts of abnormal synchronous discharge by a network of neurons Abnormal firing appears to involve -neuronal ion channel -imbalance between excitatory and inhibitory synaptic function

*ION CHANNEL:
‡ Increase in interior negativity hyperpolarisation causes decrease in resting potential, that makes it more difficult for neurons to reach threshold and subsequently fire. After depolarisation if Na+ channels are unable to open , repetitive firing is diminished.

‡

EXISTING MEDICATION
All the present medication is based upon Altered ion conduction of1. 2. 3. 4. 5. 6.     Inc. NA++ contrac.- inactivation Dec. CA++ current thalamus Inc. GABA Dec. Glutamate- NMDA, AMDA; Kainic Acid Dec. Glutamate- NMDA, AMDA; Kainic Acid Genetic Mech-: ECT VNS DBS TMS

NEED FOR NEW MEDICATION TECHNIQUE
‡ Epilepsy is a collection of diverse disorders that together affect about 1% of the general population. ‡ The disease is characterised by neuronal hyper-excitability, and is associated with mutations in greater than 50 genes involved in nerve communication or energy production, head trauma, tumours and infectious diseases. ‡ The global market for epilepsy drugs in 2007 was valued at US$15.7 billion ‡ Present epilepsy therapies are moderately successful, although no currently available drugs treat the underlying disease. ‡ Most drugs have side-effect tolerability problems. ‡ Approximately 25 - 30% of patients receive no therapeutic benefits from current treatments, representing a large unmet medical need.

NORMAL SYNAPSIS:
pre-synaptic terminal Action potential causes opening of voltage gated calcium channel

increase in calcium concentration in pre synaptic vessicle

exocytosis of vessicle

release of neurotransmitter

In most synapses, there are a very limited number of vesicles that respond quickly to increases in calcium and undergo exocytosis. If the frequency of action potentials is high, the synapse will quickly be depleted of fast-responding vesicles. The number of fast-responding vesicles has been termed the readily releasable pool (RRP) of synaptic vesicles.

To replenish the RRP

ENDOCYTOSIS(which involves many proteins and enzymatic step)

Dynamin (is one enzyme involved in endocytosis)

It helps pinch the vesicle off from the plasma membrane The action of dynamin to pinch off a vesicle for endocytosis requires the conversion of GTP to GDP

DYNAMIN
Dynamin is essential for clathrin-dependent coated vesicle formation. It is required for membrane budding at a late stage during the transition from a fully formed pit to a pinched-off vesicle. Dynamin may also fulfill other roles during earlier stages of vesicle formation. We have screened about 16,000 small molecules and have identified 1, named here dynasore, that interferes in vitro with the GTPase activity of dynamin1, dynamin2, and Drp1, the mitochondrial dynamin, but not of other small GTPases. Dynasore acts as a potent inhibitor of endocytic pathways known to depend on dynamin by rapidly blocking coated vesicle formation within seconds of dynasore addition. Two types of coated pit intermediates accumulate during dynasore treatment, U-shaped, half formed pits and O-shaped, fully formed pits, captured while pinching off. Thus, dynamin acts at two steps during clathrin coat formation; GTP hydrolysis is probably needed at both steps.

FUNCTION OF DYNAMIN
Dynamin is a multifunctional enzyme involved in:  Endocytosis of clathrin-coated vesicles and caveolae  Phagocytosis  Podosome formation  some forms of actin rearrangement, centrosomal cohesion, and cytokinesis. Its GTPase activity is integrally involved in these processes. There are three dynamin genes-: ‡ Dynamin I in neurons ‡ Dynamin II being ubiquitously expressed ‡ Dynamin III in neurons and testes

DYNAMIN
Dynamin is a 100-kDa GTPase with multiple domains. Some of these have known functions1. The N-terminal GTPase domain, the PH domain that binds phosphatidylinositol lipids 2. The C-terminal proline arginine-rich domain (PRD) that binds to several SH3 domain-containing dynamin partners

DYANMIN INBITION IN EPILEPSY:
ROLE OF DYNAMIN IN EPILEPSY: ‡ GTPase dynamin is the most attractive pharmacological target in a large collection of proteins involved in endocytosis and vesicle trafficking. ‡ The GTPase Dynamin represents a potentially highly efficacious target that indirectly modulates neurotransmitter loading. ‡ Dynamin I - A target for epilepsy - key driver of neuronal SVE, which retrieves empty SVs for later refilling after neurotransmitter release that occurs during synaptic firing. A common feature of all AEDs is a reduction in synaptic transmission. so the drugs having dyanmin inhibition activity is useful in epilepsy.

DYNAMIN IThe rapid synaptic vesicle endocytosis (SVE) likely mediated by dynamin I that follows vesicle exocytosis in nerve terminals. SVE serves to retrieve empty synaptic vesicles for later Refilling. A target for epilepsy - key driver of neuronal SVE, which retrieves empty SVs for later refilling after neurotransmitter release that occurs during synaptic firing. Dynamin I has two known functions in SVE; as an instigator of proteinprotein interactions for SVE and as a provider of mechanochemical force for clathrin-coated pit vesicle internalisation

DYNAMIN IIReceptor-mediated endocytosis (RMEa) mediated by dynamin II which is initiated upon ligand binding to cell surface receptors and occurs via clathrin-coated pits inmost cells. A target for cancer - is required for at least two different functions; receptormediated endocytosis (RME) and cytokinesis. RME is a process critical to internalisation of hormones or transmitters that bind to cell surface receptors (e.g., receptor tyrosine kinase epidermal growth factor receptor (EGFR)). Dynamin II provides mechanochemical force to internalise clathrin-coated pits containing these molecules after receptor stimulation. CMRI/UoN have designed small molecules to inhibit Dynamin II. Recent evidence has emerged that dynamin II plays a key role in the development of human diseases;10 Charcot-Marie-Tooth disease (CMT)11 and in autosomal dominant centronuclear myopathy (CNM).12 Alzheimer s disease, Huntington s disease, Stiff-person syndrome, Lewy body dementias, and Niemann-Pick type C disease are illustrative of human pathological conditions within which defects in endocytosis have been implicated.7,13-15 Endocytic pathways are also utilized by viruses, toxins and symbiotic microorganisms to gain entry into cells.16 Inhibition of the GTPase activity of dynaminmay be a useful strategy to prevent infection by such pathogens.

DYNAMIN: A NOVEL TARGET AND FIRST-INCLASS DRUGS
‡ The GTPase dynamin is the most attractive pharmacological target in a large collection of proteins involved in endocytosis and vesicle trafficking. ‡ . Dynamin has three isoforms which are required for SVE and other endocytosis-mediated processes. ‡ The structural and functional differences between these isoforms provides for the development of selective and potent first-in-class modulators that can be used as novel treatments for epilepsy (Dynamin I) and other diseases associated with endocytosis (Dynamin II)

DYNAMIN INHIBITORS

IMINOCHROMENE INHIBITORS OF DYNAMINS I AND II GTPASE ACTIVITY AND ENDOCYTOSIS 
Iminochromene ( iminodyn) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC50 values of 260nMto 100 M), with N,N(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N(ethane-1,2-diyl)-bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N(ethane-1,2-diyl)bis(7,8-dihydroxy- 2-iminochromene-3-carboxamide) (23) (IC50 values of 330(70, 450(50, and 260(80nM, respectively) being the most potent.  Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP.  Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I).  The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.

SYNTHESIS OF IMINODYNS
N,N-(Ethane-1,2-diyl)bis(2-imino-2H-chromene-3-carboxamide) (14)N,N-(Ethane-1,2-diyl)bis(2-cyanoacetamide) (0.194 g, 1 mmol), 2-hydroxybenzaldehyde (0.244 g, 2 mmol), PROCEDURE: 1. 3 Drops of piperidine was taken 2. 10ml of ethanol was added to it and was refluxed for 2 hrs 3. After cooling ,filtering and washing with cold ether ,then recrystallining with ethanol gave a off-white solid 4. mp 293-295 C.

CONCLUSION 
Hereinwe have developed a newchemical class of dynamins I and II GTPase inhibitors based on an iminochromene scaffold. We call these new classes of dynamin inhibitors the iminodyns. They are the first reported nanomolar potent dynamin inhibitors. The most potent of these were imino-dyn 17, iminodyn-22, and iminodyn-23 which are about 5-fold more potent than our previously reported dynoles and are over 400 times more potent than dynasore 400 times more potent than dynasore. These analogues bind to the GTPase domain and exert their influence on dynamin via a mechanism that is uncompetitive with GTP binding. SAR reveals similarities and surprising differences from those previously determined for dimeric tyrphostins. The iminodyns have allowed the incorporation of Bis-T s cyano moieties as imines exocyclic to a second fused ring, showing for the first time that removal of the cyanomoieties of Bis-T is feasible, and indeed with the iminodyns improves activity.

REFERENCES
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