vasoactive-intestinal-peptide and Carotid-Stenosis

Reduced blood flow to the brain induces cerebral ischaemia, potentially causing central injury and peripheral complications including gastrointestinal (GI) dysfunction. The pathophysiology behind GI symptoms is suspected to be neuropathy in the enteric nervous system (ENS), which is essential in regulating GI function. This study investigates if enteric neuropathy occurs after cerebral ischaemia, by analysing neuronal survival and relative numbers of vasoactive intestinal peptide (VIP) and neuronal nitric oxide synthase (nNOS) expressing neurons in mouse ileum after three types of cerebral ischaemia. Focal cerebral ischaemia, modelled by permanent middle cerebral artery occlusion (pMCAO) and global cerebral ischaemia, modelled with either transient occlusion of both common carotid arteries followed by reperfusion (GCIR) or chronic cerebral hypoperfusion (CCH) was performed on C56BL/6 mice. Sham-operated mice for each ischaemia model served as control. Ileum was collected after 1-17 weeks, depending on model, and analysed using morphometry and immunocytochemistry. For each group, intestinal mucosa and muscle layer thicknesses, neuronal numbers and relative proportions of neurons immunoreactive (IR) for nNOS or VIP were estimated. No alterations in mucosa or muscle layer thicknesses were noted in any of the groups. Loss of myenteric neurons and an increased number of VIP-IR submucous neurons were found in mouse ileum 7 days after pMCAO. None of the global ischaemia models showed any alterations in neuronal survival or relative numbers of VIP- and nNOS-IR neurons. We conclude that focal cerebral ischaemia and global cerebral ischaemia influence enteric neuronal survival differently. This is suggested to reflect differences in peripheral neuro-immune responses.

Topics: Animals; Brain Ischemia; Carotid Stenosis; Cell Death; Cerebrovascular Circulation; Disease Models, Animal; Ileum; Infarction, Middle Cerebral Artery; Male; Mice, Inbred C57BL; Myenteric Plexus; Neurons; Nitric Oxide Synthase Type I; Time Factors; Up-Regulation; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide, acting as a neuromodulator and neuroprotective peptide in the CNS after injuries. We have previously described that pituitary adenylate cyclase-activating polypeptide (PACAP), another member of the same peptide family, is retinoprotective in ischemic lesions. The aim of this study was to investigate the protective potential of VIP in bilateral common carotid artery occlusion (BCCAO)-induced ischemic retinal lesion. Two-month-old rats were subjected to BCCAO and treated with intravitreal VIP injection. Their retinas were processed for histology after 2 weeks of survival. We measured the number of the cells/100 μm of the ganglion cell layer and the thickness of each layer such as the outer nuclear, outer plexiform, inner nuclear, and inner plexiform layers as well as that of the whole retina. We found that treatment with 1,000 pmol VIP, but not 100 pmol VIP, had significant protective effects in BCCAO-injured retina, as shown by the morphometric analysis. Comparing the neuroprotective effects of VIP and PACAP in BCCAO-operated retinas, PACAP was more effective, already protective at 100-pmol doses. Similar to other studies, we found that VIP must be given at least in 10 times more concentration than PACAP to achieve a similar degree of neuroprotection in the retina.

Topics: Animals; Apoptosis; Carotid Artery, Common; Carotid Stenosis; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Intravitreal Injections; Ischemia; Male; Models, Neurological; Neuroprotective Agents; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Wistar; Retinal Degeneration; Retinal Neurons; Retinal Vessels; Retinitis; Time Factors; Vasoactive Intestinal Peptide