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.
Highlights
Epileptogenesis is a dynamic and multifactorial process of molecular, cellular, and functional reorganization in the brain that follows the precipitating events or insults that lead to epilepsy—a disease which is characterized by spontaneous recurrent seizures (SRS) [1]
In the previous series of experiments, we demonstrated that MI pretreatment significantly decreases severity of acute seizures induced either by pentylentetrazolium (PTZ) or by kainic acid (KA) in experimental animals [7, 8]
In support of our hypothesis, we demonstrate that (i) frequency and duration of SRS are significantly reduced in MI-treated animals as compared to KA+Saline (KA+SAL) group during 8 weeks after status epilepticus (SE); (ii) expression of sodium-myoinositol transporter (SMIT) is upregulated in the hippocampus in KA+SAL and in KA+MI groups, with the significantly highest level in MI-treated group; (iii) expression of leucine-rich repeat-containing 8A (LRRC8A) is increased only in KA+SAL group whereas in MI-treated animals LRRC8A maintains the same control level; (iv) various changes in mi-RNA spectrum have been observed in the KA+SAL and KA+MI groups comparing to control groups
Summary
Epileptogenesis is a dynamic and multifactorial process of molecular, cellular, and functional reorganization in the brain that follows the precipitating events or insults that lead to epilepsy—a disease which is characterized by spontaneous recurrent seizures (SRS) [1]. At present there are no drugs available that could effectively prevent the process of epileptogenesis or modify the disease in humans or experimental animals [1,2,3]. We hypothesized that the MIinduced normalization of biochemical alterations during epileptogenesis can lead to disease modification and decrease SRS frequency and duration in the chronic phase of epilepsy. We investigated whether 4 week post-SE MI administration exerted long-term effects on the frequency and duration of SRS after the termination of the treatment, and this was accompanied by the molecular changes in the hippocampus. It is noteworthy that some of the miRNAs in MI-treated group remain on the same level as in the control group
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