Title:Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis
Volume: 17
Issue: 3
Author(s): Si Chen, Qiao Liao, Ke Lu, Jinxia Zhou, Cao Huang and Fangfang Bi*
Affiliation:
- Department of Neurology, Central South University, Xiangya Hospital, Changsha, Hunan,China
Keywords:
Autophagy, proteostasis, movement disorders, neurodegenerative diseases, transgenic rodents, Riluzole.
Abstract:
Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically
characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding
protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed
medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic
mice are existing animal models for mechanistic/translational research into ALS.
Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene
(TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to
control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF)
gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene
showed progressive worsening of mobility and grip strength, along with loss of motor neurons,
microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the
spinal cord.
Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not
mitigate the behavioral deficits nor alter the neuropathologies in the transgenics.
Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and
neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development
of the behavioral and histopathological phenotypes in this new transgenic rodent model of
ALS.
