The inhibitory effect of minocycline on radiation-induced neuronal apoptosis via AMPKα1 signaling-mediated autophagy

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.

AMPKα1 overexpression improves postoperative cognitive dysfunction in aged rats through AMPK‐Sirt1 and autophagy signaling

“…Enhanced autophagy in the hippocampus is reportedly able to improve cognitive impairment in rats . AMPKα1‐induced autophagy is a key mechanism for minocycline to protect neurons from radiation‐induced apoptosis . In the present study, overexpression of AMPKα1 resulted in significant increase in LC3‐II/LC3‐I ratio and Beclin1 protein levels, and a significant decrease in p62 protein levels, in hippocampus of rats with POCD, suggesting that overexpression of AMPKα1 can activate hippocampal autophagy in POCD rats.…”

“…A study has suggested that AMPKα1 knockdown in neuronal cells abolished Tanshinone IIA‐induced AMPK activation and neuroprotection against oxygen‐glucose deprivation . Minocycline reportedly protects primary neurons from radiation‐induced apoptosis via enhancing AMPKα1‐mediated autophagy . However, whether and how AMPKα1 participates in POCD remains largely unknown.…”

“…AMPKα1 activation can be induced by minocycline, an antibiotic that mitigates long‐term memory loss in rats . AMPKα1 subunits have neuroprotective effects against human α‐synuclein toxicity in nigral dopaminergic neurons .…”

“…AMPKα1 is a key subtype of the AMPK α subunit that plays major roles in regulating metabolism, cell growth, and autophagy . Several research show that AMPKα1 regulates different autophagy processes in neurons, including a neuroprotective role in Alzheimer's disease . Silent information regulator factor 2‐related enzyme 1 (Sirt1) is a NAD + ‐dependent protein deacetylase that exerts neuroprotective effects in neurodegenerative diseases .…”

Neurocognitive Decline Following Radiotherapy: Mechanisms and Therapeutic Implications

“…Minocycline is a tetracycline antibiotic with inhibitory effects on the brain's microglia and is currently being investigated as treatment for depression [70]. In preclinical studies, radiation-induced neuronal apoptosis was significantly inhibited in rats (WB single dose of 20 Gy), leading to decreased apoptosis of newborn neurons and improved cognitive performance [71], effects that were activated by enhancement of radiation-induced AMPKα1-mediated autophagy [72]. A recent study in mice with neural-specific deletion of the autophagy related 7 (Atg7) gene, WB irradiated with a single dose of 6 Gy, showed prevention of IR-induced neural stem and progenitor cell death, suggesting autophagy as a possible target to counteract IR-induced neural cell death and related neurocognitive dysfunction [73].…”