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

Melinda Paizs,László Siklós,József I Engelhardt,Caterina Bendotti,Massimo Tortarolo

doi:10.3109/17482968.2011.584627

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a multifactorial [1], multisystem [2], non-cell autonomous disease [3]
Using the non-competitive amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) receptor inhibitor, we modestly reduced the loss of motor neurons (MNs) in the lumbar spinal cord of SOD1-G93A mice, while the morphology of the remaining MNs, and especially that of the dendrites was well preserved by the treatment [9]
At 19 weeks of age, the MNs from the vehicle-treated mutant SOD1 Tg mice displayed similar increases in the volume density of the electron-dense deposits (EDDs) to those from the 12-week-old animals relative to the wild-type mice (5.13 Ϯ 0.70% vs. 3.15 Ϯ 0.39%; p ϭ 0.014) (Figure 2B), but a comparison with the corresponding talampanel-treated mutant SOD1 Tg mouse group demonstrated that talampanel was non-effective (4.88 Ϯ 0.13%; p ϭ 0.721) (Figure 2B)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a multifactorial [1], multisystem [2], non-cell autonomous disease [3]. Different competitive [8] or non-competitive [9,10] AMPA receptor inhibitors have been reported to prolong the survival of transgenic (Tg) mice with mutant Cu/Zn superoxide dismutase (SOD1) when administered before the onset of motor impairment. Using the non-competitive AMPA receptor inhibitor, we modestly reduced the loss of MNs in the lumbar spinal cord of SOD1-G93A mice, while the morphology of the remaining MNs, and especially that of the dendrites was well preserved by the treatment [9]. As AMPA receptor-mediated excitotoxicity on MNs in in vitro paradigms is thought to be mediated by an excessive calcium influx at the level of the dendrites, we hypothesized that the beneficial effect of AMPA receptor inhibitors could be a result of a reduced permeability to calcium. The drug used in our previous study belongs in the class of active

Methods

Results

Conclusion