Abstract
The search for viable, effective treatments for acute stroke continues to be a global priority due to the high mortality and morbidity. Current therapeutic treatments have limited effects, making the search for new treatments imperative. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-established cytoprotective neuropeptide that participates in diverse neural physiological and pathological activities, such as neuronal proliferation, differentiation, and migration, as well as neuroprotection. It is considered a promising treatment in numerous neurological diseases. Thus, PACAP bears potential as a new therapeutic strategy for stroke treatment. Herein, we provide an overview pertaining to the current knowledge of PACAP, its receptors, and its potential neuroprotective role in the setting of stroke, as well as various mechanisms of neuroprotection involving ionic homeostasis, excitotoxicity, cell edema, oxidative stress, inflammation, and cell death, as well as the route of PACAP administration.
Highlights
Stroke is a catastrophic disease associated with high mortality and morbidity in humans [1]
The PAC1 expression decreased in the hippocampus granule cells within the first 3 days after global ischemia [89], but increased 3-28 days after global ischemia in hippocampal astrocytes [90, 91]. These results indicated that the Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 signaling pathway may play an important role in the hippocampal neurorepair process in the subacute and chronic stages after global ischemia
Considering that there is plenty of overlap pertaining to the pathophysiological mechanisms of hemorrhagic and ischemic stroke, we boldly proposed that the PACAP treatments will attenuate both types of stroke by exerting the following neuroprotective effects: anti-apoptosis [43], anti-inflammation [46], anti-oxidative stress [100], anti-excitotoxicity [101], ionic equilibrium maintenance [102], and vascular protection [103] (Fig. 2)
Summary
Stroke is a catastrophic disease associated with high mortality and morbidity in humans [1]. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with a structure that has remained evolutionarily conserved since the protochordate It was initially discovered in hypothalamic tissue three decades ago [6, 7], and is considered as a member of the vasoactive intestinal peptide (VIP)/ glucagon/secretin family due to its high homology with VIP on the N-terminus amino acid sequence [7]. It was found to function as a potential effective therapeutic for various chronic nervous system disorders, such as post-traumatic stress disorder [11], multiple sclerosis [12], migraine [13], and even dry eye syndrome[14] It was generally upregulated in several types of acute pathological conditions, including cerebral ischemia [15], intracerebral hemorrhage (ICH) [16], subarachnoid hemorrhage (SAH) [17], and traumatic brain injury [18]. While VPAC1 is mainly present in the cerebral cortex and hippocampus, VPAC2 is found primarily in the thalamus, hypothalamus, hippocampus, central nucleus of amygdala, and brainstem [27, 28]
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