Hsp70 inducer,17-allylamino-demethoxygeldanamycin,provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is the predominant cause of mortality in young adults and children living in China. TBI induces inflammatory responses; in addition,tumor necrosis factor-α (TNF-α),interleukin-1β (IL-1β),and IL-6 are important pro-inflammatory cytokines. Considering the observation that Hsp-70 overexpression can exert neuroprotec­tion,identifying a drug that is able to induce the upregulation of Hsp70 has the potential to be a promising therapy for the treatment of neurological diseases. Thus,the present study assessed the clinical effectiveness of an anticancer drug and Hsp70 activator,17-allylamino-demethoxygeldanamycin (17-AAG),to evaluate its potential as a treatment for patients with TBI. The aim of present study was to determine the neuroprotective effects of 17-AAG following trauma and to investigate the underlying mechanisms of action. To establish rat models,rats were subjected to a controlled cortical impact injury and randomly divided into vehicle or 17-AAG groups. In the 17-AAG group,rats were administered with an intraperitoneal injection of 17-AAG (80 mg/kg) immediately following the establishment of TBI. The motor function was measured using Neurologic Severity Score,and neuronal death was evaluated using immunofluorescence. The expression levels of GLT-1,Bcl-2 and Hsp-70 were detected by western blot analysis and the expression levels of inflammatory cytokines were quantified using ELISA. The present study determined that 17-AAG significantly reduced brain edema and motor neurological deficits (P<0.05),in addition to increasing neuronal survival. The aforementioned findings are associated with a downregulation of the expression levels of pro-inflammatory cytokines TNF-α,IL-1β and IL-6. Conversely,no significant changes of glutamate transporter-1 expression were observed. The present results suggest that 17-AAG treatment may provide a neuroprotective effect by reducing inflammation following TBI.