Abstract
Due to an increasing concern about radiation-induced cognitive deficits for brain tumor patients receiving radiation therapy, developing and evaluating countermeasures has become inevitable. Our previous study has found that minocycline, a clinical available antibiotics that can easily cross the blood brain barrier, mitigates radiation-induced long-term memory loss in rats, accompanied by decreased hippocampal neuron apoptosis. Thus, in the present study, we report an unknown mechanism underlying the neuroprotective effect of minocycline. We demonstrated that minocycline prevented primary neurons from radiation-induced apoptosis and promoted radiation-induced autophagy in vitro. Moreover, using an immortalized mouse hippocampal neuronal cell line, HT22 cells, we found that the protective effect of minocycline on irradiated HT22 cells was not related to DNA damage repair since minocycline did not facilitate DNA DSB repair in irradiated HT22 cells. Further investigation showed that minocycline significantly enhanced X-irradiation-induced AMPKα1 activation and autophagy, thus resulting in decreased apoptosis. Additionally, although the antioxidant potential of minocycline might contribute to its apoptosis-inhibitory effect, it was not involved in its enhancive effect on radiation-induced AMPKα1-mediated autophagy. Taken together, we have revealed a novel mechanism for the protective effect of minocycline on irradiated neurons, e.g. minocycline protects neurons from radiation-induced apoptosis via enhancing radiation-induced AMPKα1-mediated autophagy.
Highlights
Cranial radiation therapy (RT) is often used in the treatment for primary and metastatic brain tumors as well as head and neck cancers
PVDF membrane was first probed with p-ATM antibodies, stripped and probed with ATM antibodies. (b) Western blotting showing that minocycline did not have any effect on p53 activation in irradiated HT22 cells. p53 and GAPDH were probed from different parts of the same PVDF membrane. (c) Western blotting showing that minocycline pretreatment inhibited the induction of γ-H2AX in irradiated HT22 cells
To confirm that the inhibitory effect of minocycline on radiation-induced neuronal apoptosis was associated with its enhancive effect on radiation-induced autophagy, we further explored whether minocycline would display the same protective effect on irradiated HT22 cells deficient in autophagy
Summary
Cranial radiation therapy (RT) is often used in the treatment for primary and metastatic brain tumors as well as head and neck cancers. Undergo cranial irradiation[9], and hippocampal dosimetry may predict the occurrence of neurocognitive deficit after RT10, etc All of these suggest that radiation-induced damage to the hippocampus may play a critical role in radiation- induced cognitive impairment. Our previous study has discovered that minocycline, a clinical available second-generation tetracycline antibiotics that can cross the blood brain barrier, could significantly improve the cognitive performance of rats receiving WBI, and this protective effect of minocycline was accompanied by its inhibitory effect on radiation-induced hippocampal neuronal apoptosis[12]. We determined the effects of minocycline on radiation-induced apoptosis and autophagy in primary neurons in vitro. (c) Western blotting showing that minocycline pretreatment inhibited the induction of γ-H2AX in irradiated HT22 cells. Cell cycle distribution was measured using flow cytometry. (e) Minocycline did not affect the kinetics of appearance and disappearance of 53BP1
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