Long-Term Effects of Myoinositol on Behavioural Seizures and Biochemical Changes Evoked by Kainic Acid Induced Epileptogenesis

Abstract

Epilepsy is one of the most devastating neurological diseases and despite significant efforts there is no cure available. Occurrence of spontaneous seizures in epilepsy is preceded by numerous functional and structural pathophysiological reorganizations in the brain—a process called epileptogenesis. Treatment strategies targeting this process may be efficient for preventing spontaneous recurrent seizures (SRS) in epilepsy, or for modification of disease progression. We have previously shown that (i) myoinositol (MI) pretreatment significantly decreases severity of acute seizures (status epilepticus: SE) induced by kainic acid (KA) in experimental animals and (ii) that daily post-SE administration of MI for 4 weeks prevents certain biochemical changes triggered by SE. However it was not established whether such MI treatment also exerts long-term effects on the frequency of SRS. In the present study we have shown that, in KA-induced post-SE epilepsy model in rats, MI treatment for 28 days reduces frequency and duration of behavioural SRS not only during the treatment, but also after its termination for the following 4 weeks. Moreover, MI has significant effects on molecular changes in the hippocampus, including mi-RNA expression spectrum, as well as mRNA levels of sodium-MI transporter and LRRC8A subunit of the volume regulated anionic channel. Taken together, these data suggest that molecular changes induced by MI treatment may counteract epileptogenesis. Thus, here we provide data indicating antiepileptogenic properties of MI, which further supports the idea of developing new antiepileptogenic and disease modifying drug that targets MI system.

Myo-Inositol Limits Kainic Acid-Induced Epileptogenesis in Rats

“…There was no significant difference between KA + MI and CON + SAL groups [One-way ANOVA treatment factor F(2,14) = 4.42, p = 0.037, KA + SAL vs. CON + SAL group T = 2.92, p = 0.019, Figure 5]. Thus, KA-induced epileptic state is associated with upregulation of LRRC8 protein levels which corresponds to previously shown increased mRNA levels [16], whilst MI treatment attenuates this increase.…”

“…We also demonstrated that, in KA-induced post-SE epilepsy model in rats, MI reduces frequency and duration of behavioural (motor) SRS during and even 4 weeks after the treatment [16]. In addition, MI had normalizing effect on mi-RNA expression spectrum, mRNA levels of sodium-MI transporter and LRRC8A subunit of the volume regulated anionic channel [16].…”

“…KA + SAL vs. CON + SAL group T = 7.67, p = 0.000 and KA + SAL vs. KA + MI group T = 3.03, p = 0.016 for both comparisons DF = 8]. Thus the PTPRR protein changes are reciprocal to miR-6216 changes in the hippocampus [16], which may indicate that miR-6216 could be implicated in the processes of KA-induced The mean levels of PTPRR as measured by WB were the highest in the KA + SAL group as compared to CON + SAL and KA + MI groups. No significant differences were detected between CON + SAL and KA + MI groups (Figure 6C).…”

“…We have previously shown that in the hippocampus, the LRRC8 mRNA is increased in KA + SAL group as compared to KA + MI and CON + SAL groups [16]. Here, we asked whether these changes in mRNA were also translated in the LRRC8 protein levels since this may not follow the mRNA changes in a linear way [22].…”

Myo-Inositol and Its Derivatives: Their Emerging Role in the Treatment of Human Diseases

“…The treatment reduced both the frequency and duration of spontaneous recurrent seizures, the main character of epilepsy. In addition, MI had significant effects on SMIT1 and leucine rich repeat-containing 8A, a component of volume regulated anionic channel (Tsverava et al, 2019).…”