Antiepileptic Activity of Ziconotide as a Neuronal Calcium Channel Blocker: Experimental and Clinical Features abstract
Epilepsy is a chronic non-communicable neurological disorder with high prevalence that affects around 50 million people worldwide and is caused by abnormal electrical activity in the brain. Normal brain function depends on the proper balance between excitatory and inhibitory neurotransmitters, and their imbalance leads to the abnormalities such as epileptic seizures. The crucial role of the calcium ions and glutamate-induced calcium influx via N-methyl-D-aspartate receptors (NMDARs) in neuropathological conditions is widely mentioned in various studies. During the neuropathological conditions such as traumatic brain injury and its neurobehavioral sequelae including possible seizure and epilepsy, excessive glutamate release and subsequent abnormal NMDA - stimulated calcium accumulation in postsynaptic neurons is thought to contribute to a cascade of cellular events that lead to the neuronal cell death. On the other hand, most epileptic and anxious patients that treated with the first-line drugs demonstrate tolerance, dependency and addiction to the remedy. Therefore pharmaceuticals with lower adverse effects and more efficacies in neuronal disturbance including seizure and convulsion are highly desired.
Ziconotide is the small peptide originated and synthesized by cone snails as a component of paralytic venoms.
Ziconotide induces neuroprotection at least by two pathways: (1) direct blocking of calcium entry by acting on the N-type calcium channels and (2) restricting calcium entrance via postsynaptic NMDARs due to inhibition of release of the presynaptic excitatory neurotransmitter, glutamate. Other neuroprotective mechanisms of ziconotide are believed to be competitive inhibition of neuronal nicotinic acetylcholine receptors (nAChR) and blocking N-type VDCC via intracellular signaling mediated by gamma-aminobutyric acid receptors (GABABR). It is concluded that ziconotide represents neuroprotective including anti-seizure activity in human and animal models of neuronal damages but in human clinical trials, it seems necessary to improve the convenience of peptide drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.