An Experimental Study On The Ameliorating Effect Of Terazoisn On Whole-brain Irradiation-induced Cognitive Dysfunction

Objective:Radiation therapy is an important(sometimes even the only)treatment for primary gliomas,brain metastases,and head and neck tumors.However,normal brain tissue is inevitably exposed due to anatomical factors and may cause cognitive decline in some patients.Terazosin-a long-acting selective α1 adrenergic receptor antagonist that stimulates glycolysis and increases cellular ATP levels by enhancing the activity of phosphoglycerate kinase 1(Pgk1).Studies have shown that terazosin has a certain neuroprotective effect in Parkinson’s disease,and the pathogenesis of central neurodegenerative diseases(such as Parkinson’s disease)has some similarities compared with that of radiation-induced brain injury.Therefore,this study aims to observe whether terazosin can ameliorate cognitive impairment induced by whole-brain irradiation(WBI),to investigate the effect of terazosin administration on hippocampal neuron apoptosis and microglia activation,providing a preliminary experimental basis for the potential implication of terazosin in the prevention and treatment of radiation-induced brain injury.Methods:A total of 64 sprague-dawley rats were randomly divided into the untreated control group(CN),the terazosin group(CT),the radiation group(RN)and the radiation plus terazosin group(RT),with 16 rats in each group.Terazosin was administered via oral gavages directly into the stomach by 0.1mg/kg·d and was initiated one week before WBI and maintained for 2 months.Whole-brain irradiation was administered at a single dose of 20 Gy.24 of the rats were sacrificed at 3 hours post-WBI to investigate the effect of terazosin administration on the apoptosis of hippocampal neurons in the early stage of irradiation using immunohistochemistry for caspase-3 and relative markers for juvenile neurons(Doublecortin,DCX).The open field test and the Morris water maze(MWM)test were used to assess the the anxiety level,the spatial learning and memory of the other 40 rats.Neurogenesis was determined by double-label immunofluorescence staining for bromodeoxyuridine(BrdU)and NeuN 2 months post WBI.Neuroinflammation was assayed by single-label immunofluorescence staining for ionized calcium binding adaptor molecule-1(Iba-1)2 months post WBI.Results:1.Neither WBI nor terazosin affected the locomotor activity and anxiety level of rats.2.The latency to reach the platform in the radiation group was longer than that of the other groups,while the radiation plus terazosin group did not experience a delay compared with the non-irradiated controls in the MWM test.Terazosin intervention improved the short-term memory retention of irradiated rats.3.After terazosin treatment,the number of DCX positive cells increased 35%compared with the radiation group 3 hours after irradiation,suggesting that terazosin may have a certain protective effect on hippocampal juvenile neurons in the early stage of irradiation.4.Hippocampal neurogenesis was inhibited after 20 Gy WBI,and terazosin may not significantly rescue neurogenesis disorders induced by irradiation.5.20 Gy WBI induced neuroinflammation via microglia activation.After the terazosin intervention,the number of Iba positive cells in the radiation plus terazosin group decreased 49%compared with the radiation group.Terazosin intervention may inhibit WBI-induced neuroinflammation via microglia activation.Conclusions:1.Ionizing radiation has been shown to induce cognitive decline due to hippocampal cell proliferation inhibition,neurogenesis disorder and hippocampal neuron damage;2.It is initially shown that terazosin may improve short-term spatial learning and memory after WBI.3.Terazosin may reduce the hippocampal juvenile neuron loss and inhibit neuroinflammation via microglia activation,which can alleviate whole-brain irradiation-induced cognitive dysfunction to a certain extent.