PACAP Stimulates Functional Recovery after Spinal Cord Injury through Axonal Regeneration

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide expressed in the central nervous system. Although many studies have shown a neuroprotective effect of PACAP, the mechanism of PACAP in the treatment of spinal cord injury (SCI) is yet to be elucidated. The purpose of this study was to examine the efficacy and underlying mechanism of PACAP in a mouse SCI model where PACAP was delivered via a biodegradable hydrogel. When PACAP or saline was delivered immediately after SCI, the functional motor recovery 14 days after SCI was significantly improved in the PACAP group compared with that in the saline group. Expression levels of messenger RNA (mRNA) for collapsin response mediator protein 2 (CRMP2), a factor related to axonal regeneration, were increased in the PACAP group 14 days after SCI compared with those in the saline group. A significantly increased number of CRMP2-positive cells were observed around the injury lesion in the PACAP group, while CRMP2 co-labeling with neuronal and oligodendrocyte markers was detected in intact spinal cord. Fourteen days after SCI, anterograde tracing revealed that a significantly increased number of neuronal fibers extended caudally from the lesion epicenter in the PACAP group. These results suggest that PACAP stimulates functional motor recovery after SCI through axonal regeneration mediated by CRMP2.

Signalling Alterations in Bones of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Gene Deficient Mice

“…It has been demonstrated that PACAP can prevent the harmful effect of oxidative stress [ 16 , 17 ], trigger the activation of anti-inflammatory processes and can have a positive role during ischemic conditions [ 18 ]. PACAP is also known to activate the immune system [ 19 ] and to induce tissue regeneration [ 20 ]. It plays an important role in the development of different organs, regulates chondrogenesis and spermatogenesis [ 16 ], and influences the development of the central nervous system [ 10 , 21 ].…”

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

“…Among the well-established and most intensively studied actions are PACAP’s neurotrophic and neuroprotective effects. PACAP has been shown to protect neurons against various noxious stimuli in vitro and in vivo [6,7,8] For example, PACAP is protective in traumatic brain [9] and spinal cord injury [10], in global and focal cerebral ischemia [6], in models of Huntington’s disease [11], and in Parkinson’s disease [12,13,14]. …”

Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP)

“…PACAP exerts multiple functions through three specific receptors - PACAP receptor 1 (PAC1R) and two VIP/PACAP receptors [ 13 , 14 ]. Exogenous and endogenous PACAP decreases neuronal cell death after ischemia, SCI, and other neuronal disorders [ 15 - 20 ]. PACAP also contributes to suppress inflammatory/immune responses.…”