Reductions in Hydrogen Sulfide and Changes in Mitochondrial Quality Control Proteins Are Evident in the Early Phases of the Corneally Kindled Mouse Model of Epilepsy

Cho, Christi; Zeigler, Maxwell; Mizuno, Stephanie; Morrison, Richard S.; Totah, Rheem A.; Barker‐Haliski, Melissa

doi:10.3390/ijms23031434

Cited by 11 publications

(8 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Corneal Kindled Mouse (CKM): For the 60 Hz corneal kindling protocol, mice (n=40) were stimulated with an initially benign electrical current (60 Hz, sinusoidal pulse; 3.0 mA) delivered for 3 sec via corneal electrodes or sham-kindled (n=10). Seizures were scored upon a 5-point rating scale consistent with the Racine scale in amygdala-kindled rats and routinely used by our group for corneal kindled mice [47], wherein; 1 = jaw chomping and vibrissae twitching, 2 = head bobbing and Straub tail, 3 = unilateral forelimb clonus, 4 = bilateral forelimb clonus and hind-limb rearing, 5 = bilateral forelimb clonus and rearing followed by loss of righting reflex. Twice daily stimulations continued for each mouse until it achieved the criterion of 5 consecutive Racine stage 5 seizures, whereby the mouse was considered "fully kindled".…”

Section: Methodsmentioning

confidence: 99%

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

Zierath¹,

Mizuno²,

Barker‐Haliski³

2023

Preprint

View full text Add to dashboard Cite

The mechanisms of treatment-resistant epilepsy remain unclear. We have previously shown that frontline administration of therapeutic doses of lamotrigine (LTG), which preferentially inhibits the fast-inactivation state of sodium channels, during corneal kindling of mice promotes cross-resistance to several other antiseizure medicines (ASMs). However, whether this phenomenon extends to monotherapy with ASMs that stabilize the slow inactivation state of sodium channels is unknown. Therefore, this study assessed whether lacosamide (LCM) monotherapy during corneal kindling would promote future development of drug-resistant focal seizures in mice. Male CF-1 mice (n=40/group; 18-25 g) were administered an anticonvulsant dose of LCM (4.5 mg/kg, ip), LTG (8.5 mg/kg, ip), or vehicle (0.5% methylcellulose) twice daily for two weeks during kindling. A subset of mice (n=10/group) were euthanized 1 day after kindling for immunohistochemical assessment of astrogliosis, neurogenesis, and neuropathology. The dose-related antiseizure efficacy of distinct ASMs, LTG, LCM, carbamazepine, levetiracetam, gabapentin, perampanel, valproic acid, phenobarbital, and topiramate was then assessed in remaining kindled mice. Neither LCM nor LTG administration prevented kindling: 29/39 vehicle-exposed mice were kindled; 33/40 LTG-exposed mice were kindled; and 31/40 LCM-exposed mice were kindled. Mice administered LCM or LTG during kindling became resistant to escalating doses of LCM, LTG, and carbamazepine. Perampanel, valproic acid, and phenobarbital were less potent in LTG- and LCM-kindled mice, whereas levetiracetam and gabapentin retained equivalent potency across groups. Notable differences in reactive gliosis and neurogenesis were also appreciated. This study indicates that early, repeated administration of sodium channel blocking ASMs, regardless of inactivation state preference, promotes pharmacoresistant chronic seizures. Inappropriate ASM monotherapy in newly diagnosed epilepsy may thus be one driver of future drug-resistance, with resistance being highly ASM class-specific.

show abstract

Section: Methodsmentioning

confidence: 99%

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

Zierath¹,

Mizuno²,

Barker‐Haliski³

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Mitochondrial stress and MQC are involved in the pathogenesis of epilepsy. The levels of MQC-related proteins OPA1, MFN2, MFF, and Drp1 are elevated in the mice models of acute maximal electroshock and 6 Hz 44 mA seizure ( Cho et al, 2022 ). MQC-related serine peptidase LONP1 is up-regulated in the mitochondria during status epilepticus (SE), and LONP1 knockdown enhances SE-induced mitochondrial apoptosis in neuron ( Kim et al, 2021 ).…”

Section: Aberrant Mitochondrial Quality Control and Brain Disordersmentioning

confidence: 99%

Mitochondrial quality control in the brain: The physiological and pathological roles

et al. 2022

View full text Add to dashboard Cite

The human brain has high energetic expenses and consumes over 20% of total oxygen metabolism. Abnormal brain energy homeostasis leads to various brain diseases. Among multiple factors that contribute to these diseases, mitochondrial dysfunction is one of the most common causes. Maintenance of mitochondrial integrity and functionality is of pivotal importance to brain energy generation. Mitochondrial quality control (MQC), employing the coordination of multiple mechanisms, is evolved to overcome many mitochondrial defects. Thus, not surprisingly, aberrant mitochondrial quality control results in a wide range of brain disorders. Targeting MQC to preserve and restore mitochondrial function has emerged as a promising therapeutic strategy for the prevention and treatment of brain diseases. Here, we set out to summarize the current understanding of mitochondrial quality control in brain homeostasis. We also evaluate potential pharmaceutically and clinically relevant targets in MQC-associated brain disorders.

show abstract

“…Moreover, epilepsy reduces antioxidant enzyme levels (NADH or FADH) and increases ROS production ( 89 ). Indeed, nitric oxide synthase expression is increased in the early phases of epileptogenesis in mice ( 90 ). Acute, seizure-induced reductions in hydrogen sulfide levels are detected in young adult mice during the development of the corneal kindled model of epilepsy, and similar studies in aged mice are needed ( 90 ).…”

Section: Potential Neurobiological Mechanismsmentioning

confidence: 99%

“…Indeed, nitric oxide synthase expression is increased in the early phases of epileptogenesis in mice ( 90 ). Acute, seizure-induced reductions in hydrogen sulfide levels are detected in young adult mice during the development of the corneal kindled model of epilepsy, and similar studies in aged mice are needed ( 90 ). Thus, oxidative stress is highly associated with both aging and epilepsy.…”

Section: Potential Neurobiological Mechanismsmentioning

confidence: 99%

“…All these detrimental factors increase ROS accumulation ( 78 , 91 ). Mitochondrial mRNA and protein expression are dynamically altered in response to epileptogenesis in the young-adult brain ( 90 ), but whether this is similarly impacted by age remains to be determined. Unfortunately, few studies have sufficiently assessed how aging and epilepsy additively or synergistically influence mitochondrial membrane integrity dynamics or quality control.…”

Section: Potential Neurobiological Mechanismsmentioning

confidence: 99%

See 1 more Smart Citation

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy

et al. 2022

Self Cite

View full text Add to dashboard Cite

Older people represent the fastest growing group with epilepsy diagnosis. For example, cerebrovascular disease may underlie roughly 30–50% of epilepsy in older adults and seizures are also an underrecognized comorbidity of Alzheimer's disease (AD). As a result, up to 10% of nursing home residents may take antiseizure medicines (ASMs). Despite the greater incidence of epilepsy in older individuals and increased risk of comorbid seizures in people with AD, aged animals with seizures are strikingly underrepresented in epilepsy drug discovery practice. Increased integration of aged animals into preclinical epilepsy drug discovery could better inform the potential tolerability and pharmacokinetic interactions in aged individuals as the global population becomes increasingly older. Quite simply, the ASMs on the market today were brought forth based on efficacy in young adult, neurologically intact rodents; preclinical information concerning the efficacy and safety of promising ASMs is not routinely evaluated in aged animals. Integrating aged animals more often into basic epilepsy research may also uncover novel treatments for hyperexcitability. For example, cannabidiol and fenfluramine demonstrated clear efficacy in syndrome-specific pediatric models that led to a paradigm shift in the perceived value of pediatric models for ASM discovery practice; aged rodents with seizures or rodents with aging-related neuropathology represent an untapped resource that could similarly change epilepsy drug discovery. This review, therefore, summarizes how aged rodent models have thus far been used for epilepsy research, what studies have been conducted to assess ASM efficacy in aged rodent seizure and epilepsy models, and lastly to identify remaining gaps to engage aging-related neurological disease models for ASM discovery, which may simultaneously reveal novel mechanisms associated with epilepsy.

show abstract

Reductions in Hydrogen Sulfide and Changes in Mitochondrial Quality Control Proteins Are Evident in the Early Phases of the Corneally Kindled Mouse Model of Epilepsy

Cited by 11 publications

References 69 publications

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

Mitochondrial quality control in the brain: The physiological and pathological roles

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy

Contact Info

Product

Resources

About