Reviving mitochondrial bioenergetics: A relevant approach in epilepsy

Singh, Simranjeet; Singh, Thakur Gurjeet; Rehni, Ashish K.; Sharma, Vivek; Singh, Manjinder; Kaur, Rupinder

doi:10.1016/j.mito.2021.03.009

Cited by 38 publications

(16 citation statements)

References 146 publications

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“…From the above findings, the onset of seizures and the severity of tonic-clonic seizures were reduced significantly (p < 0.05) and dose-dependently in mice treated with CS (100 & 200 mg/kg; (p.o. )), when compared with the PTZ-and pilocarpine-treated groups, which was in line with previously published studies [34][35][36].…”

Section: Discussionsupporting

confidence: 92%

“…Seizure-induced neuronal death is associated with alterations in neurotrophin-dependent pathways, excitotoxicity, apoptotic pathways, the inflammatory cascade, and oxidative stress [33][34][35]. In epilepsy, the brain dependency on oxygen consumption makes it more vulnerable to oxidative injury, which is exhibited by elevated oxygen free radicals [36]. In addition, the excessive repetitive seizures inducement of oxidative brain tissue injury is marked by shrinkage of neuronal tissue, causing a decrease in the extracellular space leading to the shift of ionic concentration between the intracellular and extracellular region, i.e., by increasing the intracellular space of ionic concentration as compared to the extracellular region of the neuronal cell [4][5][6].…”

Section: Discussionmentioning

confidence: 99%

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

Singh

et al. 2021

Molecules

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Singh

et al. 2021

Molecules

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“…Cytochrome C (Cyt-C) is an electron transporting protein, upon receiving the apoptosis signal, Cyt-C is rapidly released from the mitochondrion. Cytosolic Cyt-C can activate Caspase-3 and eventually leads to apoptosis [27]. Caspase-3 is the downstream pathway of cell apoptosis and can be activated when cells apoptosis happens [28].…”

Section: Discussionmentioning

confidence: 99%

Novel dihydroartemisinin derivative Mito-DHA5 induces apoptosis associated with mitochondrial pathway in bladder cancer cells

Xiao

Lin

et al. 2022

BMC Pharmacol Toxicol

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Background Bladder cancer is the second most common genitourinary malignancy and the eleventh most common cancer worldwide. Dihydroartemisinin (DHA), a first-line antimalarial drug, has been found to have potent antitumor activity. In our previous study, a novel dihydroartemisinin derivative Mito-DHA5 synthesized in our laboratory has a stronger anti-tumor activity than DHA. In this study, we investigated the apoptotic effect of Mito-DHA5 on bladder cancer T24 cells and molecular mechanisms underlying. Methods Antitumor activity in vitro was evaluated by MTT, wound healing and cloning formation assays. Mitochondrial membrane potential (MMP) was detected by JC-1 probe and ROS levels were measured by specific kit. The expression of caspase-3, cleaved-caspase3, mitochondrial Cyt-C, Bcl-2, Bax and PARP in T24 cells was evaluated by Western blotting. Results The results showed that Mito-DHA5 reduced cell viability with an IC50 value of 3.2 µM and induced T24 cell apoptosis in a dose-dependent manner, increased the production of ROS and decreased MMP. Mito-DHA5 could down-regulate the expression of Bcl-2, mitochondrial Cyt-C, Caspase-3, PARP and up-regulate the expression of Bax and cleaved Caspase-3. Conclusions These data suggested that Mito-DHA5 had a potent inhibitory effect on T24 bladder cancer cell growth and induced these cells apoptosis associated with mitochondrial pathway.

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“…Oxidative stress is a condition in which endogenously or exogenously produced pro‐oxidant species—for example, reactive oxygen and nitrogen species (ROS and RNS, respectively)—overwhelm the antioxidant defense during basal conditions (Sies et al., 2017 ; Sies & Cadenas, 1985 ). Dysfunction of the body's response to oxidative stress results in the accumulation of damaged biomolecules and cellular structures (Singh et al., 2021 ), which are hallmarks of cell senescence. In this scenario, mitochondria play a fundamental role as they are the main intracellular source of oxygen free radicals along with being one of the main targets of ROS and RNS (Balaban et al., 2005 ).…”

Section: Discussionmentioning

confidence: 99%

A postpartum enriched environment rescues impaired cognition and oxidative markers in aged mice with gestational inflammation

et al. 2022

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Introduction Previous studies have shown that gestational inflammation can accelerate age‐associated cognitive decline (AACD) in maternal mice; enriched environments (EEs) have been reported to protect normally aging mice from AACD and improve mitochondrial function. However, it is unclear whether the nitrosative stress‐related proteins tet methylcytosine dioxygenase 1 (TET1) and S‐nitrosoglutathione reductase (GSNOR) are involved in the accelerated aging process of gestational inflammation and whether EEs can slow this process. Methods In this study, CD‐1 female mice on the 15th day of pregnancy were injected with bacterial lipopolysaccharide (50 μg/kg; LPS group) or an equivalent amount of normal saline (CON group) from the abdominal cavity for 4 consecutive days. Twenty‐one days after delivery, half of the LPS‐treated mice were randomly selected for EE until the end of the behavioral experiment (LPS‐E group). When the female rats were raised to 6 months and 18 months of age, the Morris water maze (MWM) was used to detect spatial learning and memory ability; RT‐PCR and Western blots were used to measure the mRNA and protein levels of hippocampal TET1 and GSNOR. Results As for the control group, compared with 6‐month‐old mice, the spatial learning and memory ability of 18‐month‐old mice decreased, and the hippocampal TET1 and GSNOR mRNA and protein levels were decreased. Gestational inflammation exacerbated these age‐related changes, but an EE alleviated the effects. Pearson's correlation analysis indicated that performance during the learning and memory periods in the MWM correlated with the levels of hippocampal TET1 and GSNOR. Conclusions Our findings suggest that gestational inflammation accelerates age‐related learning and memory impairments and that postpartum EE exposure could alleviate these changes. These effects may be related to hippocampal TET1 and GSNOR expression.

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Reviving mitochondrial bioenergetics: A relevant approach in epilepsy

Cited by 38 publications

References 146 publications

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

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

Novel dihydroartemisinin derivative Mito-DHA5 induces apoptosis associated with mitochondrial pathway in bladder cancer cells

A postpartum enriched environment rescues impaired cognition and oxidative markers in aged mice with gestational inflammation

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