Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures

Patel, Manisha

doi:10.1016/j.freeradbiomed.2004.08.021

Cited by 305 publications

(225 citation statements)

References 97 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…However, previous studies suggest that CBD exerts an activity‐dependent biphasic control over Ca 2+ levels (Ryan et al, 2009); hence, it is likely that in our experiments, CBD treatment of epileptic rats exerted a neuroprotective function by preventing intracellular Ca 2+ overloading during hyperactivity, thus halting oxidative stress. This would trigger mitochondrial oxidation (Hajnoczky et al, 2006), contributing to the degenerative process of neurons (Liang et al, 2000; Patel, 2004; Waldbaum et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

British J Pharmacology

View full text Add to dashboard Cite

Background and PurposeA non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.Experimental ApproachElectrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.Key ResultsBath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.Conclusions and ImplicationsOur data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.

show abstract

Section: Discussionmentioning

confidence: 99%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…These ketone bodies also inhibit glutamate-induced mitochondrial reactive oxygen species generation [14]. Oxidative stressors may contribute to the development of epilepsy (reviewed in [15]). Therefore, β-hydroxybutyrate and acetoacetate may prevent neuronal damage from free radicals and confer neuroprotective (and possibly antiepileptogenic) effects.…”

Section: Do Ketone Bodies Mediate the Effects Of The Ketogenic Diet?mentioning

confidence: 99%

The Neuropharmacology of the Ketogenic Diet

Hartman

Gąsior

Vining

et al. 2007

Pediatric Neurology

268

158

View full text Add to dashboard Cite

The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.

show abstract

“…Seizures cause extensive formation of reactive oxygen species (ROS) and oxidative stress [112,113]. Oxidative damage to cell proteins, lipids, and DNA may explain long-term debilitating consequences of seizures to the brain [81,96,107,114].…”

Section: Seizures Neuronal Injury and Cerebral Vascular Functionmentioning

confidence: 99%

“…During seizures, the glutamate concentration in the brain can be elevated to a cytotoxic level [83,117]. Excitatory neurotransmitters at excitotoxic concentrations (10 -4 -10 -3 M) act as endogenous neurotoxins [47,48,83,95,113,117,119]. Disruption of Ca 2+ homeostasis and oxidative stress appear to be key mechanisms in glutamate cytotoxicity [113,119,120].…”

Section: Seizures Neuronal Injury and Cerebral Vascular Functionmentioning

confidence: 99%

“…Excitatory neurotransmitters at excitotoxic concentrations (10 -4 -10 -3 M) act as endogenous neurotoxins [47,48,83,95,113,117,119]. Disruption of Ca 2+ homeostasis and oxidative stress appear to be key mechanisms in glutamate cytotoxicity [113,119,120]. Neurotoxic effects of glutamate are mediated via glutamate receptors, and the most rapid neuronal injury results from activation of NMDA receptors and AMPA/Kainate receptors and massive Ca 2+ entry [81,95,113].…”

Section: Seizures Neuronal Injury and Cerebral Vascular Functionmentioning

confidence: 99%

See 1 more Smart Citation

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

View full text Add to dashboard Cite

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

show abstract

Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures

Cited by 305 publications

References 97 publications

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

The Neuropharmacology of the Ketogenic Diet

Cerebroprotective Functions of HO-2

Contact Info

Product

Resources

About