PACAP and its receptor in the brain of SIDS and after hypoxia and nicotine exposures

Abstract

Introduction: Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide found ubiquitously throughout the body, is important for respiratory regulation, amongst other things, and regulates its role via its pituitary adenylate cyclase activating polypeptide receptor 1 (PAC1). PACAP null mice have a reduction in their respiratory rate and aberrant responses to hypoxic insults, while PAC1 knockout mice exhibit cardiorespiratory failures. Up to 50% of these knockout mice die at 2-weeks of age. Given these similarities to what is reported in Sudden Infant Death Syndrome (SIDS), this study compares the expression differences for PACAP and PAC1 in the SIDS infant brain and in piglet models emulating the two major risk factors in SIDS, cigarette exposure and re-breathing expired gases due to prone sleeping. Methods: Immunohistochemistry was carried out to detect the expression of PACAP and PAC1 which were then quantified using computerised image analyses. The infant dataset consisted of 32 SIDS compared to 12 non-SIDS and regions of the brain studied included midbrain, pons and rostral medulla of the brainstem, plus the hippocampus. The piglet dataset consisted of piglets exposed to intermittent hypercapnia hypoxia (IHH) for 1day (n=7) or 2-4 days (n=6), nicotine (NIC) (n=7) and combined NIC+IHH (n=6). The brain region analysed was the caudal medulla. Results: From the infant dataset, a decrease in PAC1 in the arcuate nucleus of SIDS infants was found compared to non-SIDS, and an increase in PACAP in the midbrain dorsal raphe. For the piglets, this thesis found a decrease in PACAP after acute exposure to IHH (1day) in the dorsal motor nucleus of vagus (DMNV), nucleus of the solitary tract (NTS) and gracile nucleus (GRAC). PAC1 expression was reduced in the NTS. Little expression change was noted in NIC exposed piglets, with a decrease in PAC1 in the DMNV noted only. Furthermore, a decrease in PACAP was noted in the hypoglossal (XII), DMNV, GRAC and cuneate (CUN) in combined NIC+IHH groups, but this was related to the IHH exposure given these changes were seen in the IHH alone- thus, NIC itself, had no influence. Conclusion: Abnormalities in PACAP and PAC1 in SIDS infants are present and may play a role in the pathophysiology of SIDS. Lack of similarities in the changes for PACAP and PAC1 between the piglet models and SIDS, suggests an alternate pathway(s) to IHH and nicotine exposure is at play amongst SIDS.