VIPergic neuroprotection in epileptogenesis: challenges and opportunities

Abstract In mesial temporal lobe epilepsy (MTLE), seizures typically arise in the hippocampus or other mesial temporal lobe structures. The aetiology of MTLE epileptogenesis in still unknown, yet putative precipitating events such as trauma, complex febrile seizures, status epilepticus, inflammatory insults, or ischemia have been implicated. MTLE is commonly associated to a high degree of hippocampal sclerosis (HS) leading to frequent anti-epileptic drug refractoriness. Thus, the aim of recent therapeutic strategies has shifted from control of symptomatic seizures to putative prevention of epileptogenic processes. Vasoactive intestinal peptide (VIP) acts as a neurotransmitter, neurotrophic or neuroprotective factor in the central nervous system (CNS), also displaying anti-inflammatory and neurogenic actions. In the hippocampus, a brain area implicated in learning and memory, VIP released from basket cells and/or interneuron-selective interneurons controls GABAergic transmission and pyramidal cell activity influencing hippocampal-dependent synaptic plasticity (long-term potentiation and long-term depression) and cognition. VPAC1 receptor activation enhances hippocampal synaptic transmission by fostering disinhibition, while stimulation of VPAC2 receptors favours pyramidal cell excitability. Interestingly, VIP released from interneurons has potent anti-inflammatory actions, participates in the maintenance of the blood-brain barrier integrity, and strengthens neurogenesis. VPAC1 and VPAC2 receptors play differential roles in the regulation of the neuro-immune interactions. In this context, we gathered here the available information concerning the impact of VIP on neurotransmission and neuronal excitability in MTLE-HS and discuss the preventive use of selective VIP receptor ligands to abrogate epileptogenesis in MTLE-HS by controlling synaptic plasticity, neurogenesis and neuronal survival, neuroinflammation, and blood-brain barrier damage.