l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70

Abstract

l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score (p = 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly prolonged the time to the first seizure (p < 0.0001) and shortened seizure duration (p = 0.028). In addition, l-Car administration for four weeks attenuated PTZ-induced increase in the level of oxidative stress marker malondialdehyde (MDA) (p < 0.0001) and reduced the activity of catalase enzyme (p = 0.0006) and increased antioxidant GSH activity (p < 0.0001). Moreover, l-Car significantly reduced PTZ-induced elevation in protein expression of caspase-3 (p < 0.0001) and β-catenin (p < 0.0001). Overall, our results suggest a potential therapeutic role of l-Car in seizure control and call for testing these preclinical results in a proof of concept pilot clinical study.

Curcumin offsets PTZ-induced epilepsy: involving inhibition of apoptosis, wnt/β-catenin, and autophagy pathways

“…Previous studies investigated and confirmed the role of oxidative stress, apoptosis and heat shock proteins in the pathogenic mechanisms of epilepsy [6,7]. Gupta et al [8] and Hussein et al [6,7] demonstrated a significant increase in malondialdehyde (MDA) with a significant reduction in reduced glutathione (GSH) levels and catalase (CAT) activity suggesting enhanced oxidative stress in the brain tissues of epileptic rats. Also, the role of apoptosis and its signaling pathways in seizure-induced neuronal cell deaths has been demonstrated in previous experimental studies [7,9].…”

“…Details of brain tissue homogenization, tissues lysis, PAGE electrophoresis and membrane transfer and incubation with the primary and secondary antibodies were mentioned in our previous work [7]. The primary antibodies of cleaved caspase-3 (MW 17 and 19 kDa, product No.…”

“…Gupta et al [8] and Hussein et al [6,7] demonstrated a significant increase in malondialdehyde (MDA) with a significant reduction in reduced glutathione (GSH) levels and catalase (CAT) activity suggesting enhanced oxidative stress in the brain tissues of epileptic rats. Also, the role of apoptosis and its signaling pathways in seizure-induced neuronal cell deaths has been demonstrated in previous experimental studies [7,9]. Moreover, a recent study reported a significant role for autophagy in PTZ-induced epilepsy [10].…”

<p>Selenium Nanoparticles Pre-Treatment Reverse Behavioral, Oxidative Damage, Neuronal Loss and Neurochemical Alterations in Pentylenetetrazole-Induced Epileptic Seizures in Mice</p>

“…CAT activity in the hippocampal supernatant was estimated according to the method illustrated by Aebi. 34 In order to evaluate the CAT activity, the enzymatic reaction mixture (total volume 1 mL) contained 50…”

“…49 It has been shown that neuronal cells are able to produce HSPs. Accumulative evidences reported the relationship between the development of epileptic seizures and the upregulation of Hsp70 in animal models 50 and in humans. 51 The authors described the upregulation of Hsp70 as a protective effect potentiated to protect neurons against hyperexcitability coupled with the development of epileptic seizures.…”