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Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice.

ABSTRACT: Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly (p < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1β, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1β, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.

SUBMITTER: Singh S

PROVIDER: S-EPMC8622985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes.

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Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice.

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