Abstract
Background: Adropin is a peptide encoded by the energy homeostasis associated gene ( Enho ) highly expressed in the brain. Our unpublished data revealed robust effects of adropin on reducing neurovascular damage and behavioral impairments in young mice following stroke. However, it is unknown whether these protective effects of adropin are observed in aged animals after stroke. Hypothesis: Considering that aging is the most critical risk factor for stroke, we hypothesized that adropin provides neuroprotection in aged mice subjected to ischemic stroke. Methods: Aged (18-24 months old) male adropin knockout ( Enho -/- ), adropin overexpressing transgenics (AdrTg), and their corresponding control littermates were subjected to permanent middle cerebral artery occlusion (pMCAO). Adhesive removal, nesting behavior, and novel object recognition test were conducted before and up to 14 days after MCAO. Infarct volume was quantified by MRI at 14 days post-MCAO. In a separate experiment, we utilized aged male Enho -/- and AdrTg mice subjected to 30 min of transient MCAO (tMCAO). To investigate the potential therapeutic benefit of adropin in stroke, aged wild-type mice were randomly selected to receive a bolus injection of vehicle or synthetic adropin (900 nmol/kg; i.v.) at the onset of ischemia. Neurobehavioral tests were performed before and at 48h after stroke, and infarct size was measured by TTC staining at 48h. Results: Adropin deficiency consistently increased infarct volume and exacerbated neurological impairments in permanent and transient MCAO mice compared to Enho -/- . In contrast, transgenic overexpression of adropin significantly improved neurological function compared to WT mice. Also, AdrTg mice displayed better recovery of recognition memory function, whereas Enho -/- mice exhibited worse stroke outcomes compared to wild-type littermates following pMCAO. Similarly, treatment with synthetic adropin peptide resulted in a smaller stroke volume and better motor function recovery than vehicle-treated mice following tMCAO. Conclusions: These findings consistently show that transgenic overexpression of adropin or post-ischemic treatment with adropin peptide is neuroprotective in aged mice subjected to ischemic stroke.
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