Preventing Epileptogenesis with Vasoactive Intestinal Peptide (VIP) VPAC1 Receptor Ligands

Abstract

Mesial-temporal lobe epilepsy (MTLE) is a rare type of epilepsy, and yet one of the most prevalent types of symptomatic focal epilepsy with an unknown aetiology. In many cases it is associated with other comorbidities such as hippocampal sclerosis (HS). MTLE-HS has a high socioeconomic impact as many patients are refractory to anti-seizure drugs (ASDs) and surgical intervention is often the last therapeutic resource to prevent the chronic progression of recurrent complex partial seizures. Epileptogenesis comprises processes like abnormal synaptic plasticity, heightened neuronal excitability, excitotoxicity, inflammation, and neuronal cell death. Although this process has emerged as a natural target for the development of novel preventive/therapeutic alternatives to control epilepsy, it remains largely underexplored and, thus, only a few therapeutic approaches nowadays fulfil this goal. In the hippocampus, vasoactive intestinal peptide (VIP) is synthesized almost exclusively by interneurons and VIP exerts a modulatory role on synaptic transmission and synaptic plasticity in hippocampal pyramidal cells via the activation of VPAC1 receptors. Mounting evidence suggests VIPergic mechanisms are promising therapeutic targets to control epileptogenesis an hypothesis that is strengthened by the fact that MTLE-HS patients exhibit an increased number of VIP binding sites in the brain. This study aimed to investigate whether VPAC1 receptor modulators could provide neuroprotection against early changes in hippocampal synaptic plasticity following common epilepsy-triggering events to evaluate their capacity to prevent epileptogenesis, as prompted by preliminary data. For this, the effect of these VPAC1 receptor ligands on epileptogenesis were investigated using an in vivo model of MTLE-HS, where immunofluorescence confocal microscopy was used to assess VPAC1 and VPAC2 receptors expression levels and respective cellular distribution. Increased density of VIP, VPAC1 e VPAC2 receptors were observed in epileptic animals when compared to healthy controls. The assessment of the co-localization of VIP and its receptors with thepresynaptic vesicle marker (VAMP1), the microglial (Iba-1) and astrocyte (GFAP) markers and the caveolae marker (Caveolin-1), denoted mainly the absence of correlations. However, between VPAC1 and Caveolin-1, a tendency to co-localize was observed, namely on the stratum oriens of the CA3 region of the hippocampus of Epileptic rats. Nonetheless, these immunofluorescence staining experiments should be replicated in order to obtain a robust support to the results obtained. Similarly, additional functional studies should be performed to investigate what precise mechanisms underly these alterations seen in the epileptic animals.