Myo-Inositol Limits Kainic Acid-Induced Epileptogenesis in Rats

Abstract

Epilepsy is a severe neurological disease characterized by spontaneous recurrent seizures (SRS). A complex pathophysiological process referred to as epileptogenesis transforms a normal brain into an epileptic one. Prevention of epileptogenesis is a subject of intensive research. Currently, there are no clinically approved drugs that can act as preventive medication. Our previous studies have revealed highly promising antiepileptogenic properties of a compound–myo-inositol (MI) and the present research broadens previous results and demonstrates the long-term disease-modifying effect of this drug, as well as the amelioration of cognitive comorbidities. For the first time, we show that long-term treatment with MI: (i) decreases the frequency and duration of electrographic SRS in the hippocampus; (ii) has an ameliorating effect on spatial learning and memory deficit associated with epileptogenesis, and (iii) attenuates cell loss in the hippocampus. MI treatment also alters the expression of the glial fibrillary acidic protein, LRRC8A subunit of volume-regulated anion channels, and protein tyrosine phosphatase receptor type R, all expected to counteract the epileptogenesis. All these effects are still present even 4 weeks after MI treatment ceased. This suggests that MI may exert multiple actions on various epileptogenesis-associated changes in the brain and, therefore, could be considered as a candidate target for prevention of epileptogenesis.

Assessing the causal association between human blood metabolites and the risk of epilepsy

“…Using electrophysiological method, Gamkrelidze et al found that myo-inositol has a significant local seizure-suppressant effect [5]. In a recent study, several favorable effects of myo-inositol were observed in rat models, including decreasing the frequency and duration of electrographic spontaneous recurrent seizures in the hippocampus, ameliorating epileptogenesis-related spatial learning and memory deficit, and alleviating cell loss in the hippocampus [7]. Phosphoinositide signaling pathway and myoinositol action on gamma amino butyric acid-A receptors were the possible mechanisms of this protective effect [, 45, 46].…”

“…Likewise, there is a lot of research into the potential link between metabolites and epilepsy, implying that certain metabolites are involved in the development of epilepsy. Myoinositol, for instance, has been shown in experimental experiments to have a seizure-suppressing impact, indicating a potential protective role for myo-inositol in epilepsy [5,6,7]. In addition, the term "metabolic epilepsy" has been proposed by the International League Against Epilepsy (ILAE) organization, which has identified numerous metabolic issues in relation to epilepsy [8].…”

Long-term effects of myo-inositol on traumatic brain injury: Epigenomic and transcriptomic studies

“…Various conditions have been reported to benefit from MI treatment, such as depressive disorders ( Taylor et al, 2004 ), and polycystic ovary syndrome ( Unfer et al, 2017 ). Moreover, antiepileptogenic properties of MI have been shown in our previous studies performed on pharmacological (kainic acid-KA) animal models of epilepsy ( Kandashvili et al, 2022 , Tsverava et al, 2019 , Tsverava et al, 2016 ). It should be emphasized that MI has a long-term influence on KA-induced alterations since its beneficial effects are maintained for at least 1 month after its treatments end ( Kandashvili et al, 2022 , Tsverava et al, 2019 ).…”

Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats

“…12,13 Using this model, myo-inositol administered 4 h after KA injection and continued for 4 weeks reduced the occurrence and duration of SRSs without affecting the onset of epilepsy, thus documenting a disease-modifying effect independent of any activity on epileptogenesis. 14 Interestingly, this result was ascribed to the modulation of GABA A receptors, which notoriously are potentiated by neurosteroids such as allopregnanolone and pregnanolone, whereas pregnenolone sulfate displays opposite properties. 7 Other, different mechanisms could also be involved in the modification of epilepsy in KA-treated rats, for instance, neuroinflammation.…”

“…The KA model represents a very useful tool to investigate epileptogenesis and the progression of epilepsy after brain damage 12,13 . Using this model, myo‐inositol administered 4 h after KA injection and continued for 4 weeks reduced the occurrence and duration of SRSs without affecting the onset of epilepsy, thus documenting a disease‐modifying effect independent of any activity on epileptogenesis 14 . Interestingly, this result was ascribed to the modulation of GABA A receptors, which notoriously are potentiated by neurosteroids such as allopregnanolone and pregnanolone, whereas pregnenolone sulfate displays opposite properties 7 …”