Abstract
Epilepsy is considered as one of the major disabling neuropathologies. Almost one third of adult patients with temporal lobe epilepsy (TLE) do not respond to current antiepileptic drugs (AEDs). Additionally, most AEDs do not have neuroprotective effects against the inherent neurodegenerative process underlying the hippocampal sclerosis on TLE. Dysfunctions in the GABAergic neurotransmission may contribute not only to the onset of epileptic activity but also constitute an important system for therapeutic approaches. Therefore, molecules that enhance GABA inhibitory effects could open novel avenues for the understanding of epileptic plasticity and for drug development. Parawixin2, a compound isolated from Parawixia bistriata spider venom, inhibits both GABA and glycine uptake and has an anticonvulsant effect against a wide range of chemoconvulsants. The neuroprotective potential of Parawixin2 was analyzed in a model of TLE induced by a long-lasting Status Epilepticus (SE), and its efficiency was compared to well-known neuroprotective drugs, such as riluzole and nipecotic acid. Neuroprotection was assessed through histological markers for cell density (Nissl), astrocytic reactivity (GFAP) and cell death labeling (TUNEL), which were performed 24 h and 72 h after SE. Parawixin2 treatment resulted in neuroprotective effects in a dose dependent manner at 24 h and 72 h after SE, as well as reduced reactive astrocytes and apoptotic cell death. Based on these findings, Parawixin2 has a great potential to be used as a tool for neuroscience research and as a probe to the development of novel GABAergic neuroprotective agents.
Highlights
Temporal lobe epilepsy (TLE), the prevalent form of focal epilepsy, has the highest level of pharmacoresistance, since 30% of adult patients do not respond to current pharmacotherapy [1,2].In TLE, the epileptiform activity is originated in the limbic system leading to a partial complex seizure [3], which in most cases are triggered by an initial neurological injury [4]
Histological abnormalities were observed in the granular cell layer of the dentate gyrus (DG), in a lesser extent than in CA1 and CA3
The Status Epilepticus (SE) + VEH group presented an evident cellular loss compared to VEH + VEH (p < 0.001). Both SE + Pwx2 0.21 and 0.43 μM groups, SE + RIL and SE + nipecotic acid (NIP) were significantly different from
Summary
Temporal lobe epilepsy (TLE), the prevalent form of focal epilepsy, has the highest level of pharmacoresistance, since 30% of adult patients do not respond to current pharmacotherapy [1,2].In TLE, the epileptiform activity is originated in the limbic system leading to a partial complex seizure [3], which in most cases are triggered by an initial neurological injury [4]. Hippocampal sclerosis, characterized by neuronal loss, reactive astrocytosis, mossy fiber sprouting and glial proliferation [5,7,8], is a very common feature associated with TLE [9,10] These findings have been based on data from biopsies of hippocampus from human TLE patients, as well as from histological observations in experimental models of TLE [10]. It has been shown that neuronal damage in the hippocampus occurs mostly during a specific time window, with severe neuronal loss at 24 h that reaches its peak at 72 h after the initial SE [13,14] This TLE model has been widely used in the prospect of novel antiepileptic and neuroprotective compounds [15]
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