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.

Abstract

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.

• Authors: Jia-Wei Min, Yanying Liu, David Wang, Fangfang Qiao, Hongmin Wang
• Journal: Journal of neurochemistry (J Neurochem) Vol. 144 Issue 3 Pg. 336-347 (02 2018) ISSN: 1471-4159 [Electronic] England
• PMID: 29193080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 International Society for Neurochemistry.

Chemical References

• Amyloid beta-Protein Precursor
• Narcotic Antagonists
• Neuroprotective Agents
• Quinolines
• Receptors, Opioid, delta
• TAN 67
• Naltrexone
• naltrindole

Topics

• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Brain Ischemia (complications, drug therapy, metabolism)
• Cerebral Cortex (drug effects, metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Naltrexone (administration & dosage, analogs & derivatives)
• Narcotic Antagonists (administration & dosage)
• Neurons (drug effects, pathology)
• Neuroprotective Agents (administration & dosage)
• Quinolines (administration & dosage)
• Receptors, Opioid, delta (agonists)
• Stroke (complications, drug therapy, metabolism)