Animal Models of Neurological Disorders

Neurotherapeutics (2012) 9:241244 DOI 10.1007/s13311-012-0118-9

EDITORIAL

Animal Models of Neurological Disorders

Marie-Francoise Chesselet & S. Thomas Carmichael

Published online: 30 March 2012# The American Society for Experimental NeuroTherapeutics, Inc. 2012

Animal modeling of human disease is a cornerstone to basic scientific studies of disease mechanisms and pre-clinical studies of potential therapies. Rapid progress in animal modeling has led to advancements in the understanding of fundamental disease mechanisms of many central nervous system (CNS) disorders, including initial cell death and later repair in stroke [1, 2], motor and nonmotor pathologies in Parkinsons Disease [3, 4], and axonal regeneration in peripheral and optic nerve injury [5, 6], among many others. Ideally, animal modeling produces basic insights, new views of the human disease, and preclinical trials of novel therapies. Much progress has been accomplished in that direction since the earlier coverage of this topic in the issue of Neurotherapeutics in July 2005. Yet controversy and challenges in animal modeling of human CNS diseases continue to occur.

Negative views of animal modeling of neurological diseases often stem from failures in the application of an animal model to pre-clinical testing of candidate treatment molecules. In the stroke field, roughly 500 neuroprotective therapies that were seen as successful in rodent models of stroke subsequently failed at some stage of translation to humans, with only 1 treatment emerging as a new, approved therapy [7, 8]. In amyotrophic lateral sclerosis the mouse superoxide dismutase 1 (SOD1G39a) disease model has been the platform for the

testing of hundreds of candidate therapies, with only 1 therapy (riluzole) making it into clinical practice with a modest functional benefit [9]. Indeed, a meta-analysis of treatment data with this mouse model led to predictions for success with a candidate therapy (minocycline [10]), which actually made patients worse in a subsequent clinical trial [11]. Importantly, many of these failures in animal models may relate to experimental design and data analysis rather than to the models themselves [9, 12]. However, the use of models with uncertain mechanistic relevance to the human disease may also lead to disappointing results in clinical trials as illustrated by the reliance on toxin-based models for modeling Parkinsons disease and the failure of drugs that show neuroprotection in these models to provide benefits to patients...