Abstract
Cognitive impairment is one of the major symptoms in most neurodegenerative disorders such as Alzheimer’s (AD), Parkinson (PD), and Huntington diseases (HD), affecting millions of people worldwide. Unfortunately, there is no treatment to cure or prevent the progression of those diseases. Cognitive impairment has been related to neuronal cell death and/or synaptic plasticity alteration in important brain regions, such as the cerebral cortex, substantia nigra, striatum, and hippocampus. Therefore, compounds that can act to protect the neuronal loss and/or to reestablish the synaptic activity are needed to prevent cognitive decline in neurodegenerative diseases. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two highly related multifunctional neuropeptides widely distributed in the central nervous system (CNS). PACAP and VIP exert their action through two common receptors, VPAC1 and VPAC2, while PACAP has an additional specific receptor, PAC1. In this review article, we first presented evidence showing the therapeutic potential of PACAP and VIP to fight the cognitive decline observed in models of AD, PD, and HD. We also reviewed the main transduction pathways activated by PACAP and VIP receptors to reduce cognitive dysfunction. Furthermore, we identified the therapeutic targets of PACAP and VIP, and finally, we evaluated different novel synthetic PACAP and VIP analogs as promising pharmacological tools.
Highlights
Cognition is the result of the formation of functional neuronal circuits in many cerebral areas governed by a dynamic phenomenon named synaptic plasticity
This context and the capacity of Pituitary adenylate cyclaseactivating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) to cross the blood-brain barrier suggest that these neuropeptides and their receptors-mediated signaling could have promising therapeutic activity in neurodegenerative diseases
We summarize the pieces of evidence showing that PACAP and VIP administration help to preserve cognitive function in different preclinical models of Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD)
Summary
Cognition is the result of the formation of functional neuronal circuits in many cerebral areas governed by a dynamic phenomenon named synaptic plasticity. PACAP and Cognition in Neurodegenerative Diseases daily life of patients and their families This impairment is mediated by the extracellular or intracellular accumulation of protein aggregates that disrupt synaptic plasticity leading to neuronal dysfunction and/or neuronal death. Molecules able to promote synaptic plasticity or neuronal viability by the interaction and inhibition of these mechanisms in brain areas related to learning and memory could be interesting therapeutic compounds to stop the cognitive decline in neurodegenerative diseases. In rat hippocampal slices, it has been observed that PACAP and VIP exert a direct effect in synaptic transmission (Ciranna and Cavallaro, 2003) This context and the capacity of PACAP and VIP to cross the blood-brain barrier suggest that these neuropeptides and their receptors-mediated signaling could have promising therapeutic activity in neurodegenerative diseases. We review novel VIP and PACAP synthetic derivatives which could represent promising therapeutic tools for the treatment of neurodegenerative diseases
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