NPY and Gene Therapy for Epilepsy: How, When,... and Y

Abstract

Neuropeptide Y (NPY) is a neuropeptide abundantly expressed in the mammalian central and peripheral nervous system. NPY is a pleiotropic molecule, which influences cell proliferation, cardiovascular and metabolic function, pain and neuronal excitability. In the central nervous system, NPY acts as a neuromodulator, affecting pathways that range from cellular (excitability, neurogenesis) to circuit level (food intake, stress response, pain perception). NPY has a broad repertoire of receptor subtypes, each activating specific signaling pathways in different tissues and cellular sub-regions. In the context of epilepsy, NPY is thought to act as an endogenous anticonvulsant that performs its action through Y2 and Y5 receptors. In fact, its overexpression in the brain with the aid of viral vectors can suppress seizures in animal models of epilepsy. Therefore, NPY-based gene therapy may represent a novel approach for the treatment of epilepsy patients, particularly for pharmaco-resistant and genetic forms of the disease. Nonetheless, considering all the aforementioned aspects of NPY signaling, the study of possible NPY applications as a therapeutic molecule is not devoid of critical aspects. The present review will summarize data related to NPY biology, focusing on its anti-epileptic effects, with a critical appraisal of key elements that could be exploited to improve the already existing NPY-based gene therapy approaches for epilepsy.

A toolkit of highly selective and sensitive genetically encoded neuropeptide sensors

“…For example, corticotropin-releasing factor (CRF) release orchestrates the responses to stress, and CRF hyperactivity increases arousal, alters locomotion, and decreases sexual receptivity and food consumption (Binder and Nemeroff, 2010; Dedic et al, 2018; Henckens et al, 2016). Neuropeptide Y (NPY) is enriched in the arcuate nucleus and is essential for stimulating food intake (Zhang et al, 2019); it also acts as an endogenous anticonvulsant in both rodents and humans (Baraban et al, 1997; Cattaneo et al, 2020; Colmers and El Bahh, 2003). Interestingly, neuropeptides, such as ghrelin, NPY, and neurotensin (NTS), were shown to exert neuroprotective effects in Parkinson’s disease and Alzheimer’s disease (Li et al, 2019; Zheng et al, 2021).…”

Intermittent Fasting Enhances Hippocampal Npy Expression to Promote Neurogenesis Following Traumatic Brain Injury

“…Hence, we examined the Npy level in the hippocampus responding to fasting and also found an increasement. In previous studies, Npy was suggested to participate in a wide range of events, such as cognitive behavior, epilepsy, chronic stress, depression, social disorders, etc [33,34].…”

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases

“…Wide range of neurological disorders, including AD, PD, HD, Machado-Joseph disease [186,211,212], ALS [214], as well as associated inflammatory processes [168,169]. Potential anticonvulsant effects against seizures [281].…”