Talampanel reduces the level of motoneuronal calcium in transgenic mutant SOD1 mice only if applied presymptomatically

Abstract

We tested the efficacy of treatment with talampanel in a mutant SOD1 mouse model of ALS by measuring intracellular calcium levels and loss of spinal motor neurons. We intended to mimic the clinical study; hence, treatment was started when the clinical symptoms were already present. The data were compared with the results of similar treatment started at a presymptomatic stage. Transgenic and wild-type mice were treated either with talampanel or with vehicle, starting in pre-symptomatic or symptomatic stages. The density of motor neurons was determined by the physical disector, and their intracellular calcium level was assayed electron microscopically. Results showed that motor neurons in the SOD1 mice exhibited an elevated calcium level, which could be reduced, but not restored, with talampanel only when the treatment was started presymptomatically. Treatment in either presymptomatic or symptomatic stages failed to rescue the motor neurons. We conclude that talampanel reduces motoneuronal calcium in a mouse model of ALS, but its efficacy declines as the disease progresses, suggesting that medication initiation in the earlier stages of the disease might be more effective.

Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning

“…Talampanel (4) is a non-competitive AMPA antagonist, reduces motor neuronal calcium levels in SOD1 mice models if applied presymptomatically and is effective only during the early stage of the disease [44]. A phase II study with telampaneltreated 60 ALS patients demonstrated decrease in ALS Functional Rating Scale (ALSFRS), muscle strength and hand movements [45].…”

Potential Therapeutic Drugs and Methods for the Treatment of Amyotrophic Lateral Sclerosis

“…There is evidence that excess extracellular glutamate, especially via AMPA receptors, is a key factor in ALS neuropathogenesis [78]. In vivo studies of SOD1 mice models support the beneficial effects of AMPA antagonists such as talampanel [79]. However, it was demonstrated that the neuroprotective effects of talampanel were only present when it was applied during the early stage of the disease.…”

Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

“…Ceftriaxone prevents glutamate neurotoxicity, and when initiated at disease onset delays loss of muscle strength and body weight and prolongs survival [61]. Talampanel, a noncompetitive AMPA antagonist, reduces motorneuronal calcium levels if applied presymptomatically [62]. Memantine is an FDA-approved drug used for the treatment of Parkinsonism, vascular dementia, and Alzheimer’s disease.…”