Evaluating the efficacy of compound MP-010 in alleviating
neuromuscular deficits in SOD1G93A mice
In the first phase of our study, we examined the potential of MP-010 to
ameliorate motor impairments and neuromuscular dysfunction in
SOD1G93A transgenic mice. To this end, the animals
were given two different doses of MP-010 (61 and 122 mg/kg) (Fig. 2A).
Remarkably, the chronic administration of MP-010 at both doses examined
did not result in any discernible differences in body weight between
treated and vehicle groups of WT or SOD1G93A mice
(Fig. 2B). A notable increase in body weight was noted in the WT groups
compared to the SOD1G93A vehicle-treated group,
particularly at the 12 to 16-week time points (Fig. 2B). This emphasizes
the expected divergence in body weight trajectories between the WT and
SOD1G93A cohorts throughout the study.
Electrophysiological assessments during the follow-up revealed that
MP-010 treatment at a dose of 61 mg/kg prevented the decline of CMAP
amplitude compared to untreated SOD1G93A mice (Fig.
2C). Notably, at early (12 weeks), intermediate (14 weeks), and advanced
(16 weeks) disease stages of the disease, MP-010 at 61 mg/kg exerted
significant effects on CMAP amplitude preservation in the TA muscle of
SOD1G93A mice (Fig. 2C). In contrast, mice treated
with the 122 mg/kg dose did not manifest a substantial improvement
compared to the vehicle-treated group (Fig. 2C). In the PL muscle there
were no significant improvements with any of the doses of MP-010 in the
treated SOD1G93A mice (Fig. 2D).
The rotarod test was used to assess locomotion and coordination, and to
pinpoint the initiation of the symptomatic phase of the disease. The
administration of MP-010 at the dose of 61 mg/kg yielded a significant
improvement in rotarod performance at an advanced disease stage (14-16
weeks of age in SOD1G93A mice) (Fig. 2E), delaying the
onset of motor impairment by 2 weeks compared to untreated animals (13
weeks). In contrast, in accordance with the CMAP data, there was no
change in rotarod performance between SOD1G93A mice
treated with 122 mg/kg and vehicle control. The beneficial effects of
the 61 mg/kg regime were indicative of a deceleration in the progression
of the disease, highlighting the potential therapeutic impact of MP-010
on mitigating motor deficits in SOD1G93A mice.
At the end of the functional follow-up (16 weeks of age), a significant
increase in the number of innervated NMJ within the TA muscle in
SOD1G93A mice receiving MP-010 treatment at both doses
was noticed, compared to the vehicle-treated groups (Fig. 3A,B). This
finding supports the observed preservation of CMAP amplitude in nerve
conduction tests.