INTRODUCTION : Epilepsy is defined as a group of disorders of central nervous system (CNS) characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizures) of loss or disturbances of consciousness with or without characteristic body movement (convulsion), sensory or psychiatric phenomena. Epilepsy is the third most common neurological disorder affecting the world wide population. In which, the cyclic adenosine 3',5'- monophosphate (cAMP) plays a major role in the generation of seizure activity. The adenylate cyclase, an important transmembrane enzyme possesses certain activity in the brain, which promotes the intracellular level of cAMP, from adenosine triphosphate (ATP). An elevation in cAMP content has been reported in the cerebral cortex accompanying chemically induced epileptic activity Cyclic AMP plays a key function by controlling a wide variety of cellular processes, also which acts as a ubiquitous second messenger and modulator of signal transduction processes. This cAMP is generated by the action of adenylyl cyclase and degraded by hydrolysis process, which is regulated by a family of cyclic nucleotide phosphodiesterases (PDEs) . The neuronal cell signaling structure of cytoskeleton plays a vital role
in the development of seizures. Cyclic nucleotides have been extensively studied as second messengers of intracellular events initiated by activation of many types of hormone and neurotransmitter receptors. Cyclic guanosine monophosphate (cGMP) also serves as a second messenger in a manner similar to that observed with cAMP. Peptide hormones, such as natriuretic factors, activate receptors that are associated with membrane bound guanylate cyclase (GC). Receptor activation of GC leads to the conversion of GTP to cGMP. Nitric oxide (NO) also stimulates cGMP production by activating soluble GC, perhaps by binding to the heme moiety of the enzyme. Similar to cAMP, cGMP mediates most of its intracellular effects through the activation of specific cGMP dependent protein kinases (PKG). Several families of PDEs act as regulatory switches by catalyzing the degradation of cGMP to guanosine -5-monophosphate (5-GMP). AIMS : To examine and investigate the possible roles of specific inhibitors of PDE along with adenylate cyclase inhibitor, soluble guanylate cyclase activator and inhibitor in the generation of convulsive seizures.
Identification and investigation of new cGMP mediated phophodiesterase family members will offers a new strategy for improvement of brain function and for the new therapy for epilepsy in future. To examine and investigate the role of different ion channel modulator in the generation of convulsive seizures. OBJECTIVES : A family of cyclic nucleotide PDEs used to regulate the process of cAMP
generation and degradation by hydrolysis with the action of adenylyl cyclase activators
and inhibitors. Cyclic AMP plays a key task by controlling a wide variety of cellular
processs, also an elevation of cAMP content has been reported in the cerebral cortex
associated with chemically induced epileptic activity. Apart from cAMP, cGMP also
possess certain intracellular effects through the activation of specific cGMP dependent
protein kinases (PKG) by way of soluble guanylate cyclase (sGC). In view of these
findings the present study was undertaken to examine and investigate the possible roles
of specific inhibitors of PDEs along with adenylate cyclase inhibitors, soluble guanylate
cyclase activator and inhibitors to evaluate the effect on chemical convulsant and
maximal electroshock induced seizures in mice and rats.
Ion channels mediate and regulate crucial electrical functions throughout the
body. They are therapeutic drug targets for a variety of disorders and the direct cause of
unwanted side effects. In the view of these principles the present study also designed to
examine and investigate the role of different ion channel modulator such as sodium
channel modulator, calcium channel modulator, blocker and activator in the generation of
convulsive seizures. MATERIALS AND METHODS : Rolipram, Cilostazol, SQ 22536, A-350619, Methylene blue, Pentylenetetrazole
or metrazol (PTZ), Picrotoxin (PTx), Kainic acid and 10 % w/v Dimethyl sulfoxide
(DMSO) were obtained from Sigma chemical Co.(St.Louis, MO, USA), Dipyridamole,
BRL-50481 and Etazolate were bought from Tocris Bioscience (UK), Zonisamide and
Sildenafil were obtained from Sun Pharma (Mumbai, India), Amrinone was bought from
Samarth Pharma (India), Milrinone was obtained from Sanofi Synthelab Ltd (Mumbai,
India), Gabapentin was purchased from Micro labs Ltd. (Bangalore, India), Lacosamide
was bought from Cayman Chemicals (USA), Amiloride was obtained from Micro Nova
Pharmaceuicals (Bangalore, India), Amiodarone was purchased form Zydus Alidac
(Ahemedabad, India), Flecainide was obtained from Shreeji Pharma International,
(Gujarat, India), Nifedipine was purchased from Bayer India Ltd (Mumbai, India), Bay
K8644 S(-) was bought from Santa Cruz Biotechnology Inc. (USA), Isoniazid (INH) was
obtained from Fourts India Ltd (Chennai, India), Pilocarpine was bought from FDC
Limited, (Mumbai, India), Normal saline (0.9 %) received from CMC (Vellore, India),
Sterile water for injection was obtained from Nirmal Prime Health Care (Mumbai, India),
Electro Convulsiometer (Techno, India). The selection of dose for all drugs and pharmacological tools for the animal
models of epilepsy were based on the previous research work. The route of
administration of almost all the drugs and chemicals were intra peritoneal (i.p).
Statistical Analysis :
All the datas were expressed as mean ± SEM. The statistical analysis were carried
out by one way analysis of variance (ANOVA) followed by Dunnett’s test as well as
Tukey-Kramer Multiple Comparisons Test using Graphpad Instat version 3. Statistically
significant difference was ascertained by ‘P’ value which is considered significant at the
level of P<0.05 and highly significant at P<0.001.
CONCLUSION :
Thus in conclusion, phosphodiesterase(PDEs) ioszymes regulate the degradation
of cyclic GMP and cAMP a product of the guanylate cyclase and adenylate cyclase
activation and could contribute to the pathophysiology of the seizure mechanisms. PDE
enzymes are responsible for the hydrolysis of the cyclic nucleotides and therefore have a
critical role in regulating intracellular levels of the second messengers cAMP, cGMP, and
hence cell function as well as downstream cell signalling in the various body systems.
Recent evidence that the cyclic nucleotide phosphodiesterases exist in several molecular
forms and that these isozymes are unequally distributed in various tissue. Clinical signs
of epilepsy arise from the intermittent, excessively synchronized activity of group of
neurons. Different neurotransmitters and neuro-modulators are known to play a
significant role in the system of excitation. As per our study results, PDE inhibitors
works as a proconvulsant, so phosphodiesterase (PDEs) isozymes might used as anticonvulsant
molecule for better therapeutic response in future
