[P2-98] Potential Neuroprotective Versus Detrimental Effects of Flunarizine in the E815K Mouse Model of Alternating Hemiplegia of Childhood (AHC)
[Introduction] Flunarizine diminishes hemiplegic spells in AHC. However, in occasional cases, usually carrying the E815K mutation, its discontinuation is followed by severe developmental regression. It is not known if this is due to a detrimental effect of flunarizine, or to withdrawal from its beneficial effects.
[Methodology] Four groups (n=4-7/group): wild type (WT) and E815K adult mutant mice were injected with 20 mg/kg Flunarizine or vehicle intraperitoneally for 6 consecutive days, during which they were subjected daily to seizure and hemiplegia induction procedures. They underwent a battery of behavioral tests at 3 and 12 weeks.
[Results] Hemiplegia and Seizure episodes were shorter in E815K-Flunarizine mice than in E815K-Vehicle mice (Seizure: 7.044.2 seconds, 23.15.4, p=0.02; Hemiplegias: 34.719.9, 108.424.9, p=0.028). During weeks 3 and 12 the E815K-Flunarizine and E815K-vehicle groups did not differ in any of the following tests: week 3: Forelimb grip (0.540.06 N, 0.480.05, p=0.518), Balance Beam (647.6 seconds, 67.521.1, p=0.869), Novel object discrimination index (-0.090.45, -0.230.3, p=0.825), Open Field total number of crosses (38.911.9, 24.77.9, p=0.365); Week 12: Forelimb grip (0.530.03 N, 0.450.02, p=0.108, power>0.99), Open field total number of crosses (105.536.4, 22.19.7, p=0.078), Novel object discrimination index (-0.310.38, 0.010.001, p=0.462, power>0.99), and both completely failed the balance beam test p=1, power>0.99). Both groups were worse than wild type mice in tests performed at 3 weeks and 3 months (p<0.021 in all comparisons, except in discrimination index at week 3, p=0.22).
[Conclusion] Flunarizine shortened the seizure and hemiplegia spells while given, but resulted in no neuroprotection or subsequent deterioration.
[Methodology] Four groups (n=4-7/group): wild type (WT) and E815K adult mutant mice were injected with 20 mg/kg Flunarizine or vehicle intraperitoneally for 6 consecutive days, during which they were subjected daily to seizure and hemiplegia induction procedures. They underwent a battery of behavioral tests at 3 and 12 weeks.
[Results] Hemiplegia and Seizure episodes were shorter in E815K-Flunarizine mice than in E815K-Vehicle mice (Seizure: 7.044.2 seconds, 23.15.4, p=0.02; Hemiplegias: 34.719.9, 108.424.9, p=0.028). During weeks 3 and 12 the E815K-Flunarizine and E815K-vehicle groups did not differ in any of the following tests: week 3: Forelimb grip (0.540.06 N, 0.480.05, p=0.518), Balance Beam (647.6 seconds, 67.521.1, p=0.869), Novel object discrimination index (-0.090.45, -0.230.3, p=0.825), Open Field total number of crosses (38.911.9, 24.77.9, p=0.365); Week 12: Forelimb grip (0.530.03 N, 0.450.02, p=0.108, power>0.99), Open field total number of crosses (105.536.4, 22.19.7, p=0.078), Novel object discrimination index (-0.310.38, 0.010.001, p=0.462, power>0.99), and both completely failed the balance beam test p=1, power>0.99). Both groups were worse than wild type mice in tests performed at 3 weeks and 3 months (p<0.021 in all comparisons, except in discrimination index at week 3, p=0.22).
[Conclusion] Flunarizine shortened the seizure and hemiplegia spells while given, but resulted in no neuroprotection or subsequent deterioration.