Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

Abstract

Epilepsy is an intricate neurological disease where the neurons are severely affected, leading to the mortality of millions worldwide. Status epilepticus (SE), induced by lithium chloride (LiCl) and pilocarpine, is the most accepted model for epilepsy. The current work aims to unravel the mechanisms underlying the anti-epileptic efficacy of zingerone (an active ingredient of ginger), which has beneficial pharmacological activities on seizure-induced behavioral, histological, neurochemical, and molecular patterns in mice. Zingerone restored cognitive function by diminishing seizure activity, escape latency, and subsequent hippocampal damage manifested in histology. Seizures are associated with local inflammation, redox imbalance, and neural loss, confirmed by the present study of SE, and was attenuated by zingerone treatment. Nuclear factor-kappa B and its downstream signaling molecules (TNF-α, IL-1β, IL-6, NO, MPO) were activated in the LiCl-and-pilocarpine-induced group leading to inflammatory signaling, which was substantially ameliorated by zingerone treatment. The intrinsic apoptotic process was triggered subsequent to SE, as demonstrated by augmentation of cleaved caspase-3, downregulation of Bcl-2. However, zingerone treatment downregulated caspase-3 and upregulated Bcl-2, increasing cell survival and decreasing hippocampal neural death, deciphering involvement of apoptosis in SE. Therefore, zingerone plays an essential role in neuroprotection, probably by precluding oxidative stress, inflammation, and obstructing the mitochondrial pathway of apoptosis.

Zingerone Modulates Neuronal Voltage-Gated Na+ and L-Type Ca2+ Currents

“…It is therefore unlikely that the I Na and I Ca,L inhibited by ZO mainly arise from the alteration of the activity of TRP channels by ZO. Moreover, the subsequent application of reduced glutathione (GSH, 10 mM) and superoxide dismutase (SOD, 500 U/mL) failed to modify ZO-induced changes in the amplitude of the I Na and I Ca,L (data not shown), which makes it unlikely that there is a direct link between the inhibitory action of ZO on ionic currents and its antioxidative properties [ 1 , 5 , 6 , 14 ]. However, the production of reactive oxygen species was not measured in this study.…”

“…A very recent study has reported that ZO ameliorates the adverse effects of status epilepticus by blocking hippocampal neurodegeneration via the regulation of redox imbalance, inflammation, and apoptosis [ 5 ]. The blocking of the I Na and I Ca,L evidenced in the present study supports the potential of ZO to attenuate seizure activity [ 38 , 39 , 40 ].…”

“…It is widely recognized to have potent anti-inflammatory, antidiabetic, antilipolytic, antidiarrheal, antispasmodic, and anti-tumor properties [ 1 , 2 , 3 , 4 ]. ZO has also been reported to be particularly efficient at scavenging free radicals and reactive oxygen species in the body, in addition to inhibiting the enzymes involved in the generation of these reactive oxygen species [ 1 , 5 ]. Finally, it has recently been demonstrated to induce the production of reactive oxygen species linked to ZO-induced apoptotic changes in colon cancer cells [ 6 ].…”

“…The latter effect is assumed to be linked to the anti-neoplastic effect of ZO [ 11 ]. Moreover, a very recent study has reported that ZO attenuates status epilepticus by blocking hippocampal neurodegeneration via the regulation of redox imbalance, inflammation, and apoptosis [ 5 ]. Finally, it has also been shown that ZO potentially inhibits colonic motility in rats [ 12 , 13 ], and ginger extracts ameliorate both deltamethrin-induced testicular abnormalities and cypermethrin- or lambda-cyhalothrin-induced thyroid disorders in rats [ 2 , 14 , 15 , 16 ].…”

Topamax® and Ginger Oil Potential Neurotoxicity And Their Interaction in Mice Thru Oxidative Stress and Inflammatory Markers, Neurotransmitters Expression and Immunohistochemical Measurements

“…Taken together, our results led us to hypothesize that apoptosis, neuroin ammation, oxidative stress, and astrogliosis were implicated in the Topamax® apparent neurotoxicity. Oxidative stress with neuroin ammation, neural death, and abnormal connections between neurons are possible pathophysiological features [59]. Zingiber o cinale (Zingiberaceae) is used in traditional medicine as an antiepileptic alternative medication that has antioxidant activity and neuroprotective effects [60].…”