The non‐peptidic δ‐opioid receptor agonist Tan‐67 mediates neuroprotection post‐ischemically and is associated with altered amyloid precursor protein expression, maturation and processing in mice

• Published in: Journal of neurochemistry 2018-02, Vol.144 (3), p.336-347
• Main Authors: Min, Jia‐Wei, Liu, Yanying, Wang, David, Qiao, Fangfang, Wang, Hongmin
• Format: Article
• Language: English
• Subjects: Amyloid beta-Protein Precursor - metabolism; amyloid precursor protein; Animals; brain injury; Brain Ischemia - complications; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; ischemic stroke; Male; Mice, Inbred C57BL; Naltrexone - administration & dosage; Naltrexone - analogs & derivatives; Narcotic Antagonists - administration & dosage; Neurons - drug effects; Neurons - pathology; neuroprotection; Neuroprotective Agents - administration & dosage; opioid receptor; Quinolines - administration & dosage; Receptors, Opioid, delta - agonists; Stroke - complications; Stroke - drug therapy; Stroke - metabolism; Tan‐67
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14265

Tan‐67 is a selective non‐peptidic δ‐opioid receptor (DOR) agonist that confers neuroprotection against cerebral ischemia/reperfusion (I/R)‐caused neuronal injury in pre‐treated animals. In this study, we examined whether post‐ischemic administration of Tan‐67 in stroke mice is also neuroprotective and whether the treatment affects expression, maturation and processing of the amyloid precursor protein (APP). A focal cerebral I/R model in mice was induced by middle cerebral artery occlusion for 1 h and Tan‐67 (1.5, 3 or 4.5 mg/kg) was administered via the tail vein at 1 h after reperfusion. Alternatively, naltrindole, a selective DOR antagonist (5 mg/kg), was administered 1 h before Tan‐67 treatment. Our results showed that post‐ischemic administration of Tan‐67 (3 mg/kg or 4.5 mg/kg) was neuroprotective as shown by decreased infarct volume and neuronal loss following I/R. Importantly, Tan‐67 improved animal survival and neurobehavioral outcomes. Conversely, naltrindole abolished Tan‐67 neuroprotection in infarct volume. Tan‐67 treatment also increased APP expression, maturation and processing in the ipsilateral penumbral area at 6 h but decreased APP expression and maturation in the same brain area at 24 h after I/R. Tan‐67‐induced increase in APP expression was also seen in the ischemic cortex at 24 h following I/R. Moreover, Tan‐67 attenuated BACE‐1 expression, β‐secretase activity and the BACE cleavage of APP in the ischemic cortex at 24 h after I/R, which was abolished by naltrindole. Our data suggest that Tan‐67 is a promising DOR‐dependent therapeutic agent for treating I/R‐caused disorder and that Tan‐67‐mediated neuroprotection may be mediated via modulating APP expression, maturation and processing, despite an uncertain causative relationship between the altered APP and the outcomes observed. We proposed that post‐ischemic administration of Tan‐67, a δ‐opioid receptor (DOR), agonist, inhibits neuronal injury caused by ischemic stroke. Tan‐67‐mediated neuroprotection is dependent on DOR activation and is associated with suppression of ischemic stroke‐caused alterations of amyloid precursor protein (APP) expression, maturation and processing as well as β‐secretase activity. Our results suggest Tan‐67 as a promising therapeutic agent for treating ischemic stroke‐caused disorder.