Experimental clioquinol intoxication in rats: Abnormalities in optic nerves and small nerve cells of dorsal root ganglia

Ozawa, Kyoko; Saida, Kyôko; Saida, Takahiko

doi:10.1007/bf00688304

Cited by 5 publications

(1 citation statement)

References 30 publications

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“…Nevertheless, there is strong evidence that sensory fiber dysfunction is a significant feature of CQ intoxication. Repeated administration of CQ has been shown to lead to selective damage of small-diameter peripheral sensory nerve fibers, with few observable effects on larger diameter sensory or motor nerve fibers (31). Such damage is consistent with an action on TRPA1 expressed in small-diameter sensory nerve fibers.…”

Section: Discussionmentioning

confidence: 57%

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Andersson

Gentry²,

Moss³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

109

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The antifungal and amoebicidal drug clioquinol (CQ) was withdrawn from the market when it was linked to an epidemic of subacute myelo-optico-neuropathy (SMON). Clioquinol exerts its anti-parasitic actions by acting as a Cu/Zn chelator and ionophore. Here we show that local injections of CQ produce mechanical hyperalgesia and cold hypersensitivity through a mechanism involving TRPA1 in mice. We also show that CQ activates TRPA1 in a Zn 2؉ pain ͉ sensory neurons ͉ TRP channels ͉ zinc T he antifungal and amoebicidal drug clioquinol (CQ) was once widely used to treat gastrointestinal disorders, but was withdrawn from oral preparations when CQ was linked to an epidemic of subacute myelo-optico-neuropathy (SMON) in Japanese patients. Patients with SMON suffer from sensory and motor disorders and visual impairment. Thirty years after the ban of oral CQ, 40% of patients with SMON are unable to walk independently and approximately 7% suffer from visual impairment. The most common complaints, however, have been different forms of sensory impairments, such as tactile hypo-and hypersensitivity (almost 90% of patients) and dysesthesias (97%) (1). Notably, almost 50% of patients experience pain and 40% have cold sensitivity. CQ also has acute sensory effects, and studies on isolated nociceptive fibers in dogs demonstrated that CQ recruited normally quiescent fibers to become sensitive to hyperosmotic stimuli and cold (2), suggesting a direct effect on sensory nerves.CQ exerts its anti-parasitic actions by acting as a moderate affinity Cu/Zn chelator and ionophore. The ionophore activity of CQ contributes to its neurotoxicity (3, 4), but also makes it a useful drug for the treatment of acrodermatitis enteropathica, a rare genetic disorder characterized by insufficient Zn 2ϩ uptake (5, 6). More recently CQ has been shown to reduce Cu/Zn deposits and beta-amyloid accumulation in transgenic mouse models of Alzheimer's disease (7,8), findings that have led to clinical trials of CQ in Alzheimer's patients (9, 10).TRPA1 is expressed in a subpopulation of dorsal root ganglion (DRG) neurons, where it acts as a sensory receptor for environmental irritants and both oxidation and thiol-reactive compounds, some of which are produced endogenously during oxidative stress (11-15). Furthermore, TRPA1 can be activated by increasing the osmolarity of the extracellular solution (16).Transgenic mice lacking TRPA1 have a reduced sensitivity to cold stimuli and punctate mechanical stimulation (17), in addition to a reduced chemical sensitivity to irritants and oxidants (11,12,17,18). The similarity between the modalities affected by CQ in nociceptive fibers (increased sensitivity to cold stimulation and hyperosmotic solutions) and the behavioral deficits of mice lacking TRPA1 (reduced sensitivity to painful cold and mechanical stimuli) led us to examine whether CQ can induce pain behavior acutely in mice through the activation of TRPA1. ResultsPronociceptive Effects of Clioquinol. Tactile and cold hypersensitivity are very common symptoms in pati...

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Section: Discussionmentioning

confidence: 57%