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.