Epilepsy is typified by the tendency to have repeated seizures, which in Latin means ‘to strike’ as a result of sudden synchronous discharges in cerebral cortical neurons leading to troubled movements, sensation and consciousness. In epilepsy, the main focuses, there is an imbalance between the excitatory neurotransmitter such as dopamine, noradrenalin and glutamate when compare with inhibitory such as of serotonin and gamma-aminobutyric acid (GABA) via GABAA receptors, modified sodium, chloride, calcium and potassium currents.

Epilepsy is usually identified through a combination of electroencephalographic (EEG) testing and a complete examination of the state of a patient by a skilled expert of epilepsy disorder. Adults are identified with disorder merely when they have revealed recurring incidents of seizures, those who have encounter a seizure episode just one time are not thought to be epileptic [1]. Following diagnosis, patients are categorized based on the type of seizures they are exhibiting and after this treatment is given. Seizures might stay restricted to their region of starting point (“focal” or “partial” seizures) or extend to the complete hemispheres of cerebrum (“generalized” seizures).

Symptoms of the seizures firmly depend on the portions of brain which are influenced by hyperactivity. Seizures have been usually described as anunevenness between dopaminergic and serotonergic neurons and between glutamatergic (excitatory) and GABAergic (inhibitory) transmission. The neuropeptides perform an important function in modifying the brain excitability by modulating the role neurotransmission such as dopamine and serotonin. Many neuropeptides have been described to perform a function as an anticonvulsant. Irregularity in the concentration of certain neuropeptides is also reported in patients suffering from epilepsy. The classification of types of epileptic seizures are represented in the Figure 1 [3].

The living life of most adults with epilepsy still is badly influenced due to lack of awareness, support, not timely diagnosis, improper and irregular treatment, illiteracy, regulation, and improper research [2]. The deep study of the role of neurotransmitters, neuropeptides, and their receptors can serve as an important target for the development of new antileptic drugs. In this review article it has been updated the role of altered neurotransmitters and neuropeptides in epilepsy. Currently pharmacological treatment is effective only in two third patients and thus new drug targets are required [3][4].

PATHOPHYSIOLOGY / ПАТОФИЗИОЛОГИЯ

GABAA receptors, which regulate excitability, and GABA, an inhibitory neurotransmitter performs a significant part in the pathophysiology and progress of epilepsy [5][6]. Serotonin receptors by altering binding functions have been reported to ensure a robust association with anxiety and epilepsy. Currently, the Ca2+ channels which regulate the secretion at the synapse of neurotransmitters is anticipated to be concerned in the beginning of anxiety in the patients of epilepsy. The disturbance in the inhibitory control or imbalance of both is recognized to perform a chief regulatory role in disease progress [7]. The interval of excitation due to glutamate can be controlled by clearing the synaptic cleft which controls the extracellular levels, thus thwarting hyperexcitability. So the neurotransmitter transport can be seen as the important possible mechanism to decrease the concentration of the excitatory neurotransmitter in the synaptic cleft [8]. There are five types of glutamate receptors which have been identified some of them are reported to reside on neurons and the rest on to glial membranes [9]. Glutamate transporters help in the removal of excessive glutamate from the synaptic cleft resulting in synaptic inactivation [10].

By exploring the role of neurotransmitter transporters and their role in excitatory and inhibitory neurotransmission and the participation of the preeminent level of glutamate-glutamine shuttle operation for constant epileptic activity, may expose the novel perceptions that suggest that the therapeutic variations in the supply of neurotransmitters may cause reduction in seizure activities [11].

Voltage gated ion channels proper functioning is very important for the synchronous generation and propagation of action potential. So they definitely perform a function in the origin and mitigation of epilepsy. Mainly the channel involved are voltage gated sodium channels as we see that many antiepileptic drugs (AEDs) also act by suppressing these channels [12]. Other ionic channels involve are potassium, chloride, and calcium [13]. Epileptogenic agents act through voltage-gated ion channels by modifying excitatory and inhibitory neurotransmission [14].

Glutamate is the chief excitatory amino acid neuro-transmitter present in the brain. The glutamate receptors can be present presynaptically, postsynaptically, and on specific types of glial cells. The ionotropic subcategories are namely alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate receptors, are considered to perform a main function in epilepsy [15]. Agonist of these receptors induce epilepsy and antagonist suppress seizures. GABAB receptors which present postsynaptically in the neurons act as inhibitory receptors when treated with their agonists suppress the seizures in epilepsy [15].

Calcineurin (CaN) is a calcium-calmodulin-dependent pervasive protein phosphatase. It curb NMDA receptor activity and synaptic plasticity [16]. Cerebral cortex, hippocampus, and cerebellum are the main area of the brain where this phosphatase can be found in abundance [17]. Several animal models confirm the relation between CaN and epileptic seizures. It has been studied that the CaN expression was found to be enhanced in epileptic patients [18][19]. Calcineurin inhibitors namely FK-506 and cyclosporin A found to show neuroprotective effect. In status epilepticus CaN activity has been found to be enhanced in both hippocampus and cortex, further FK-506 and cyclosporin A both shown to impede the progression of kindling [20]. The pathophysiologic mechanisms of seizures are represented in Figure 2 [7][19].

There are many studies which gives evidence for the involvement of synaptic transmission disturbances of excitatory and inhibitory neurotransmitters in epilepsy. Recently, it has been evident these receptors are also expressed extrasynaptically [20]. Main extrasynaptic neurotransmitter involved are glutamate and GABA [21]. Certain ionotropic glutamate receptor are present extracellularly. The main sites where they are found to be located are cell stomata and piramidal cells. The lower level of GABA is thought to always present in extrasynaptic spaces, the receptor recognized is GABA A subtype and are specifically responsible for tonic inhibition. But recently it has been hypothesized that extra cellular receptors have a distinct existence and have a specific role in various brain functions [22]. Thus, these receptors can be further explored for new treatment strategies.

Certain recent studies gives the evidences of an enhanced level of extracellular regulated kinase (ERK) at the time of spontaneous seizure in both human and animals [23]. These ERK kinases are copiously directed in the hippocampus, although it is the part of the brain involved mainly in memory and learning but most epileptogenic also [24]. These pathways are also activated during pathological conditions namely epilepsy and brain ischaemia. p38 and ERK are included in hippocampal seizure capable to initiate epilepsy in certain animal models [25].

Hippocampus is the main site for epileptogenic activity: GABA an inhibitory neurotransmitter and serotonin undergoes decreased activity and glutamate and catecholamines shows hyperactivity. The glutamate exerting an excitotoxic action at postsynaptic neuron [26].

GABA is presynaptic inhibitory neurotransmitter having a vast distribution throughout the whole nervous system act mainly via GABAA receptors [27]. At the developmental stage of brain GABAA receptors initially function as excitatory and depolarizing present postsynaptically, after words becomes inhibitory hyperpolarizing and location is presynaptic [27]. Several of GABA agonist drugs are anticonvulsant, whereas GABA antagonists are mainly proconvulsant. Reduction of GABA synthesis is often epileptogenic. Drugs that enhance GABA-mediated inhibition and that enhances synaptic GABA are anticonvulsant [22][28][29].

Glutamate being the most ardent excitatory neuro-transmitter, its role in epilepsy has been attempted to be studied. Seizures results in elevations in extracellular glutamate, alterations in glial and neuronal manifestation of glutamate receptors and uptake transporters accounting to excitotoxic impairment. It has been studied that metabotropic glutamte receptors perform a significant function in modulating the actions depicted by ionotropic receptors in modifying the action of the epileptic focus. After pilocarpine-induced seizures, it has been found that there is down-regulation of presynaptic mGluR2/3 expression, which may promote enhanced excitability [30][31].

The noradrenalin system is concerned in the pathophysiology of several brain disorders. In the brain this neurotransmitter is involved in the process of consciousness, sleep, learning and its reminiscence. The decrease in the concentration of this neurotransmitter seems to enhance epileptic activity and enhanced concentration seems to inhibit it. Mainly antiepileptic activity is considered to be through the involvement of its alpha 2 receptors. Beyond this seizure risk is associated with certain brain disorders which are related to monoaminergic disfunctions [32].

The limbic system related seizures are mainly influenced by Dopamine modulations. Functional control of dopamine is reported to be disturbed or might also be due to improper expression of certain dopaminergic receptors. In contrast, certain antiparkinsonian drugs stimulate D2 receptors. The decrease in calcium level affects the dopamine synthesis leading to epileptic convulsions without any disturbances of a dopamine receptor [33].

It is an old observation that depression and epilepsy runs side by side. The depression is common in temporal lobe epileptic patients. Psychiatric patients are also at higher risk of epilepsy.Serotonin along with other neurotransmitters maintains a balance between an inhibitory and excitatory system in cortex [34]. The evidences provided by the animal model regarding the involvement of serotonin and its receptors might act as a potential novel target for a new category of drugs for epilepsy with new mechanism [35].

Destruction of the nicotinic receptors of the acetylcholine neurons present in the pedunculopontine tegmental nucleus are reported to involve in epilepsy. Certain acetylcholinesterase inhibitor drugs eg. soman lead to status epilepticus and seizures. These drugs enhances brain acetylcholine levels [36]. By report of literature, we can assume the association of the cholinergic system in the production of seizures and modification of key proteins associated in the cholinergic system leading to episodes of seizures. Further research can be done on the various cholinergic receptor systems regarding its involvement in epilepsy and new targets for development of newer drugs [37].

The stimulation of inhibitory presynaptic adenosine A1 receptors has been reported to show a protective effect for neurons. While the barrier of excitatory postsynaptic adenosine A2 receptors depicts a remedial response in the above disorders [23].

The neuropeptides are basically signaling molecules just like neurotransmitters but with long half-life as compared to neurotransmitters (act only for milliseconds), thus have a long time effect on neuronal activity and modulate the seizure threshold. At present only adrenocorticotropic hormone (ACTH) and thyrotropin-releasing hormone (TRH) is being popular in clinical practice for epilepsy therapy. Certain neuropeptides have seizure suppressing and the other have proconvulsive properties [38][39].

ACTH commonly known as corticotropin acts by binding the melanocortin receptors, nowadays most customarily used drug for treatment of infantile spasms. The etiology is based on the hypothesis of stress mediated release of corticotrophin-releasing hormone (CRH) neuropeptide in limbic regions of the brain. Origin place of CRH-induced seizures is amygdala spreading up to the hippocampus, here the expression of CRH receptors causes hyperexcitability by repression of after hyperpolarisation and potentiation of glutamatergic neurotransmission. ACTH mitigates the infantile spam by minimizing the production and secretion of CRH. ACTH, although is recommended therapy but with a lot of side effects so further research is required [40–42].

Dynorphins are endorphins that act through opioid receptors most actions are κ-receptor mediated. These peptides act on presynaptic receptors and inhibit the release of excitatory amino acids to reduce excitability [43].

Several studies have reported the role of galanine neuropeptide in the epilepsy. In status epilepticus, it has been reported that there is severe depletion of galanin mainly from the hippocampus region of brain. Galanine causes presynaptic inhibition of glutamatergic neurotransmission. Galanin is also interacts with serotonin. Serotonin in the hippocampus shows anticonvulsant effect. Thus, Galanin can be considered as a future target for research of new anticonvulsant therapy [44]. The neurotransmitters alterations in epilepsy are mentioned in Table 1.

It is most abundant in GABAergic interneurons of central nervous system and hippocampus, act through Y1-5 receptors, although the predominant action is on Y1, 2 and 5 [51]. It has been reported by animal studies and also in epileptic patients that Neuropeptide Y concentration is increased during seizure. It is also studied that activation of Y2 and Y5 receptors and blockage of Y1 receptors helps to slow down epileptic activity.Thus, Y2 and Y5 agonists and Y1 antagonist can be explored for epilepsy treatment [51].

Somatostatin peptide is generally expressed in GABA interneurons in the hippocampus and are of two types 14 and 28 depending upon the number of amino acid present. Somatostatin act through five distinct receptors named SST 1–5, where receptor 2-4 are considered to have anticonvulsant action. These receptors are located on granular cells and control the excitatory input that comes to hippocampus. It has been reported in various models of animals of temporal lobe epilepsy that the density of somatostatin interneurons decreases after seizure [52][53].

Substance P, basically an element of the tachykinin family was investigated for pain and nociception. It acts at the neurokinin1 receptor, by reducing inward rectifying potassium currents. Substance P has been reported to show pro-epileptic effects. During intense status epilepticus, peptides changes their expression within the hippocampus [54–57].

TRH, a tripeptide released from hypothalamus is also depicted in further brain portions namely cerebral cortex, amygdala, hippocampus, striatum and brainstem. It has been reported to show anticonvulsant properties in various models of animals and is mainly effective in the management of intractable epilepsy. It requires further research for the development of TSH analogues which are with good central nervous system permeability, high potency and metabolically more stable [58–60]. The neuropeptides, alterations and potential remedies in generalized epilepsy are enlisted in Table 2.

There are a number of other illustrations where unusual monogenic episodes of epilepsy have been examined thoroughly and management customized to the identified pathophysiological mechanism, with altering success.

There is a need to increase the quality of epilepsy research in India to understand the underlying biology of epilepsy which will further aid in devising new treatments and cure for chronic epilepsies. National and worldwide collaboration and financial support from funding organizations are needed to conduct quality research in India [75].

The usage of AED molecules has become progressively more efficient through various factors: novel technologies that ensure the better identification of the seizure disease and its underlying ground; the formulation of innovative medicines and amplified information of older ones; and the extensive usage of AED proportion determination. The selection of a drug relies greatly on precise identification of seizure type, which may decide the action of the medicine. The recent applications of AEDs used to treat epilepsy are given in Table 3.

Epilepsy is a neurological disease typified by recurring incidents of unusual neural dynamics in the central nervous system. The specific clinical indications or impairments happened through such seizures rely on the specific brain part involve in the disease. By clear finding of the brain part involved, various biomarkers involved in the atypical electrical brain action new treatment strategies can be searched. The kind of remedy suggested will rely on various factors namely the occurence and harshness of the seizures as well as the age of person, overall health and record of the medical past.