Dynorphin A (1–8) inhibits oxidative stress and apoptosis in MCAO rats, affording neuroprotection through NMDA receptor and κ-opioid receptor channels

Abstract

The contents of Dynorphin A(1–8) decreased gradually in ischemic cortices in rats and an intracerebroventricular administration of synthetic Dynorphin A(1–8) reduced the volume of cerebral infarction in our previous research. However, the specific protective mechanism is unclear and Dynorphin A(1–8) is unlikely to cross the blood-brain barrier (BBB) by noninvasive oral or intravenous administration as a macromolecule neuropeptide. In this study, intranasal administration was used to middle cerebral artery occlusion(MCAO) rats to assessed the therapeutic effects of Dynorphin A(1–8) by evaluating behavior, volume of cerebral infarct, cerebral edema ratio, histological observation. Then apoptosis neuron rate was detected by TUNEL staining. Immunohistochemical staining was carried out to explore the alteration of Bcl-2, Bax and Caspase-3. Finally, κ-opioid receptor antagonist and N-methyl-d-aspartate(NMDA) receptor antagonist were used to explore its possible mechanism. We found that MCAO rats under intranasal administration of Dynorphin A(1–8) showed better behavioral improvement, higher extent of Bcl-2, activity of SOD along with much lower level of infarction volume, brain water content, number of cell apoptosis, extent of Bax and Caspase-3, and concentration of MDA compared with those in MCAO model group and intravenous Dynorphin A(1–8) group. Administration of nor-BNI or MK-801 reversed these neuroprotective effects of intranasal Dynorphin A(1–8). In summary, Dynorphin A(1–8), with advantages of intranasal administration, could be effectively delivered to central nervous system(CNS). Dynorphin A(1–8) inhibited oxidative stress and apoptosis against cerebral ischemia/reperfusion injury, affording neuroprotection through NMDA receptor and κ-opioid receptor channels.