Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies

摘要

This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic.