冲击波暴露,军事人员听力损失和平衡功能障碍的主要原因,主要来自对机械感觉毛细胞和支持结构的直接机械损伤或间接通过过度的氧化应激。我们之前报道了HK-2,一种口服活性物质,多功能氧化还原调节剂(MFRM),在暴露于中等强度工作日噪音的大鼠中,听力损失和毛细胞损失非常有效,这可能主要是由于氧化应激而不是直接机械创伤而损害耳蜗。为了确定HK-2是否还可以保护耳蜗和前庭细胞免受主要由直接爆炸引起的机械创伤与氧化应激引起的损伤,我们将大鼠暴露于6个186dB峰值SPL的爆炸中。将大鼠分为四组:(B)单独爆炸,(BEP)爆炸加耳塞,(BHK-2)爆炸加HK-2和(BEPHK-2)爆炸加耳塞加HK-2。从爆炸暴露前7天至爆炸暴露后30天,以50mg/kg/d的剂量口服HK-2。暴露后60天收集耳蜗和前庭组织,并评估外毛细胞(OHC)的损失,内毛细胞(IHC),听神经纤维(ANF),螺旋神经节神经元(SGN)和前庭毛细胞,胞筒和半规管。在未经处理的爆炸暴露组(B)中,OHC发生了巨大的损失,IHC,ANF,SGN和前庭毛细胞仅在囊的纹状体区域。相比之下,与B组相比,用HK-2(BHK-2)处理的大鼠维持显著更少的OHC(67%)和IHC(57%)损失。OHC和IHC损失在BEPHK-2组中最小,但与BEP组没有显着差异,表明EP和HK-2之间缺乏保护性协同作用。没有损失ANF,BHK-2、BEP和BEPK-2组的SGN或囊状毛细胞。因此,HK-2不仅显著降低了OHC和IHC的损伤,但完全防止了ANF的损失,SGN和囊毛细胞。这种口服MFRM的强大保护作用使HK-2成为人体临床试验的极有希望的候选者。
Blast wave exposure, a leading cause of hearing loss and balance dysfunction among military personnel, arises primarily from direct mechanical damage to the mechanosensory hair cells and supporting structures or indirectly through excessive oxidative stress. We previously reported that HK-2, an orally active, multifunctional redox modulator (MFRM), was highly effective in reducing both hearing loss and hair cells loss in rats exposed to a moderate intensity workday noise that likely damages the cochlea primarily from oxidative stress versus direct mechanical trauma. To determine if HK-2 could also protect cochlear and vestibular cells from damage caused primarily from direct blast-induced mechanical trauma versus oxidative stress, we exposed rats to six blasts of 186 dB peak SPL. The rats were divided into four groups: (B) blast alone, (BEP) blast plus earplugs, (BHK-2) blast plus HK-2 and (BEPHK-2) blast plus earplugs plus HK-2. HK-2 was orally administered at 50 mg/kg/d from 7-days before to 30-day after the blast exposure. Cochlear and vestibular tissues were harvested 60-d post-exposure and evaluated for loss of outer hair cells (OHC), inner hair cells (IHC), auditory nerve fibers (ANF), spiral ganglion neurons (SGN) and vestibular hair cells in the saccule, utricle and semicircular canals. In the untreated blast-exposed group (B), massive losses occurred to OHC, IHC, ANF, SGN and only the vestibular hair cells in the striola region of the saccule. In contrast, rats treated with HK-2 (BHK-2) sustained significantly less OHC (67%) and IHC (57%) loss compared to the B group. OHC and IHC losses were smallest in the BEPHK-2 group, but not significantly different from the BEP group indicating lack of protective synergy between EP and HK-2. There was no loss of ANF, SGN or saccular hair cells in the BHK-2, BEP and BEPHK-2 groups. Thus, HK-2 not only significantly reduced OHC and IHC damage, but completely prevented loss of ANF, SGN and saccule hair cells. The powerful protective effects of this oral MFRM make HK-2 an extremely promising candidate for human clinical trials.