Academic journal article Journal of Rehabilitation Research & Development

Lipoic Acid and 6-Formylpterin Reduce Potentiation of Noise-Induced Hearing Loss by Carbon Monoxide: Preliminary Investigation

Academic journal article Journal of Rehabilitation Research & Development

Lipoic Acid and 6-Formylpterin Reduce Potentiation of Noise-Induced Hearing Loss by Carbon Monoxide: Preliminary Investigation

Article excerpt


One potential risk factor for the occurrence of significant hearing loss even under conditions of relatively low noise exposure is the presence of specific chemical contaminants. Organic solvents, metals, and chemical asphyxiants are all known to have ototoxic potential [1-3]. Simultaneous and even successive exposure to certain of these agents along with noise can greatly increase susceptibility to noise-induced hearing loss (NIHL) both for humans and laboratory animals [3-4].

The potentiation of NIHL by carbon monoxide (CO) exposure is particularly well established, and CO serves as a useful model because it is a common toxicant with well-studied physiological effects. A series of publications from our laboratory have demonstrated that CO elevates sensitivity to permanent NIHL such that noise exposures that normally produce no permanent auditory threshold shift yield profound loss if CO is present along with the noise [5-11]. The extent of cochlear impairment is related to CO dose [9], but the loss of outer hair cells (OHCs) tends to occur preferentially in the base (highfrequency region) of the cochlea, even when noise energy is maximal within a relatively low (4.0-8.0 kHz) frequency band [7]. CO alone does not produce persistent impairment of auditory function, although it can produce transient effects during acute exposure [12].

The acute effect of CO on hearing appears to involve an oxidative stress mechanism because the loss in function can be reduced or eliminated by administration of either a spin trap agent (phenyl-N-tert-butyl-nitrone [PBN]) or inhibition of reactive oxygen species (ROS) formation via the xanthine oxidase pathway (allopurinol) [13]. A two-step model is proposed to explain the potentiation of NIHL by CO. First, it is hypothesized that moderate levels of noise exposure initiate ROS formation, which is buffered via a homeostatic antioxidant system under normal conditions. This possibility has not been directly tested, although it is well-known that intense noise exposure can enhance production of ROS and generate oxidative stress. Second, it is hypothesized that if moderate noise exposure is combined with exposure to chemicals that either generate ROS on their own (e.g., CO) or disrupt intrinsic ROS-buffering pathways (e.g., acrylonitrile), intrinsic antioxidant pathways can become overwhelmed and the resulting oxidative stress could yield cochlear injury and dysfunction.

The ability of two antioxidant drugs, lipoic acid (LA) and 6-formylpterin (6-FP), to block the potentiation of NIHL by CO was investigated in this study. LA has a complex antioxidant action, being able to directly scavenge free radicals and also acting to regenerate other antioxidants such as glutathione and vitamins C and E [14]. LA has been shown to have significant protective effects in multiple organ systems, including the liver [15], kidneys [16], and brain [17]. In the cochlea, LA has also been shown to slow the development of topical aminoglycoside ototoxicity in guinea pigs [18], block both cisplatin- and carboplatin-induced ototoxicity in rats [1920], and reduce age-related hearing loss in mice [21].

Very limited data are available concerning the biological action of 6-FP in vivo. However, 6-FP, like many other pterins, is known to be a potent inhibitor of xanthine oxidase [22]. From in vitro studies, 6-FP can apparently have differential effects on cells. This agent can promote the generation of ROS, increase apoptosis, and suppress cell proliferation [23]. However, 6-FP also inhibits DNA fragmentation in vitro when cells are treated with tumor necrosis factor-[alpha]/actinomycin D. At the same time, 6-FP is known to scavenge superoxide anion radical ([O.sub.2.sup.-]) with an efficiency more than 100 times higher than PBN and to have a neuroprotective effect in the gerbil global brain ischemia model that also surpasses that of PBN [24]. …

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