Repurposing of Trimetazidine for amyotrophic lateral sclerosis: A study in SOD1G93A mice.
Br J Pharmacol
; 179(8): 1732-1752, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-34783031
ABSTRACT
BACKGROUND AND PURPOSE:
Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug used to treatment of coronary artery disease, trimetazidine, in SOD1G93A mice. EXPERIMENTALAPPROACH:
As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. We orally treated SOD1G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg-1 , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord. KEYRESULTS:
Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. CONCLUSION AND IMPLICATIONS In SOD1G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trimetazidina
/
Doenças Neurodegenerativas
/
Esclerose Lateral Amiotrófica
Limite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Itália