Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis.

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.

• Authors: Si Chen, Qiao Liao, Ke Lu, Jinxia Zhou, Cao Huang, Fangfang Bi
• Journal: Current neurovascular research (Curr Neurovasc Res) Vol. 17 Issue 3 Pg. 275-285 ( 2020) ISSN: 1875-5739 [Electronic] United Arab Emirates
• PMID: 32271694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• DNA-Binding Proteins
• Neuroprotective Agents
• TARDBP protein, human
• Riluzole

Topics

• Amyotrophic Lateral Sclerosis (drug therapy, genetics, pathology)
• Animals
• DNA-Binding Proteins (genetics)
• Disease Models, Animal
• Humans
• Neuroprotective Agents (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Rats, Transgenic
• Riluzole (therapeutic use)
• Treatment Outcome