Molecular mechanisms of sex differences in epilepsy and seizure susceptibility in chemical, genetic and acquired epileptogenesis

Reddy, Doodipala Samba; Thompson, Wesley J.; Calderara, Gianmarco

doi:10.1016/j.neulet.2021.135753

Cited by 59 publications

(44 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In humans, gender differences in epilepsy and underlying molecular mechanisms remain a well-known challenge for therapeutic approaches [ 17 , 30 ]. The accumulating data point to significant interactions between the hormonal status and other factors in epilepsy [ 17 ], which should be taken into account to improve the therapy of epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

et al. 2021

View full text Add to dashboard Cite

The disturbed metabolism of vitamins B1 or B6, which are essential for neurotransmitters homeostasis, may cause seizures. Our study aims at revealing therapeutic potential of vitamins B1 and B6 by estimating the short- and long-term effects of their combined administration with the seizure inductor pentylenetetrazole (PTZ). The PTZ dose dependence of a seizure and its parameters according to modified Racine’s scale, along with delayed physiological and biochemical consequences the next day after the seizure are assessed regarding sexual dimorphism in epilepsy. PTZ sensitivity is stronger in the female than the male rats. The next day after a seizure, sex differences in behavior and brain biochemistry arise. The induced sex differences in anxiety and locomotor activity correspond to the disappearance of sex differences in the brain aspartate and alanine, with appearance of those in glutamate and glutamine. PTZ decreases the brain malate dehydrogenase activity and urea in the males and the phenylalanine in the females. The administration of vitamins B1 and B6 24 h before PTZ delays a seizure in female rats only. This desensitization is not observed at short intervals (0.5–2 h) between the administration of the vitamins and PTZ. With the increasing interval, the pyridoxal kinase (PLK) activity in the female brain decreases, suggesting that the PLK downregulation by vitamins contributes to the desensitization. The delayed effects of vitamins and/or PTZ are mostly sex-specific and interacting. Our findings on the sex differences in sensitivity to epileptogenic factors, action of vitamins B1/B6 and associated biochemical events have medical implications.

show abstract

Section: Discussionmentioning

confidence: 99%

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

et al. 2021

View full text Add to dashboard Cite

show abstract

“…An evolving interest in this field is finding the genetic basis of differential susceptibility to PTE by identifying factors that may contribute to variable outcomes among populations exposed to the same brain injury, even though only a fraction will later develop seizures. ( Chuang and Reddy, 2018a ; Reddy et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions

Golub

Reddy

2022

Pharmacol Rev

Self Cite

View full text Add to dashboard Cite

Post-traumatic epilepsy (PTE) is one of the most devastating long-term, network consequences of traumatic brain injury (TBI). There is currently no approved treatment that can prevent onset of spontaneous seizures associated with brain injury, and many cases of PTE are refractory to antiseizure medications. Post-traumatic epileptogenesis is an enduring process by which a normal brain exhibits hypersynchronous excitability after a head injury incident. Understanding the neural networks and molecular pathologies involved in epileptogenesis are key to preventing its development or modifying disease progression. In this article, we describe a critical appraisal of the current state of PTE research with an emphasis on experimental models, molecular mechanisms of post-traumatic epileptogenesis, potential biomarkers, and the burden of PTE-associated comorbidities. The goal of epilepsy research is to identify new therapeutic strategies that can prevent PTE development or interrupt the epileptogenic process and relieve associated neuropsychiatric comorbidities. Therefore, we also describe current preclinical and clinical data on the treatment of PTE sequelae. Differences in injury patterns, latency period, and biomarkers are outlined in the context of animal model validation, pathophysiology, seizure frequency, and behavior. Improving TBI recovery and preventing seizure onset are complex and challenging tasks; however, much progress has been made within this decade demonstrating disease modifying, anti-inflammatory, and neuroprotective strategies, suggesting this goal is pragmatic. Our understanding of PTE is continuously evolving, and improved preclinical models allow for accelerated testing of critically needed novel therapeutic interventions in military and civilian persons at high risk for PTE and its devastating comorbidities. Significance Statement Post-traumatic epilepsy is a chronic seizure condition after brain injury. With few models and limited understanding of the underlying progression of epileptogenesis, progress is extremely slow to find a preventative treatment for PTE. This study reviews the current state of modeling, pathology, biomarkers, and potential interventions for PTE and comorbidities. There’s new optimism in finding a drug therapy for preventing PTE in people at risk, such as after traumatic brain injury, concussion, and serious brain injuries, especially in military persons.

show abstract

“…Benzodiazepines do not enhance tonic inhibition and thereby offer limited protection against persistent seizures and dysphoric episodes. Neurosteroids exhibit sex differences in their potency and efficacy on activation of tonic inhibition and seizure protection with greater efficacy in females than males 118,172,173 . Additional research is warranted to identify novel neurosteroid analogues for epilepsy, PPD, and related mood conditions.…”

Section: Discussionmentioning

confidence: 99%

“…The NSW concept is providing a framework for developing new therapies for perimenstrual CE. 118 Although many ASMs provide some protection in women with CE, many do not respond to common ASMs. The NSW model has been utilized to confirm that conventional ASMs have a reduced potency in protecting against catamenial seizures.…”

Section: Neuros Teroid Repl Acement Ther Apymentioning

confidence: 99%

Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women

Reddy

2021

J Neuroendocrinology

Self Cite

View full text Add to dashboard Cite

Neurosteroids are involved in the pathophysiology of many neuroendocrine disorders in women. This review describes recent advancements in pharmacology of neurosteroids and emphasizes the benefits of neurosteroid replacement therapy for the management of neuroendocrine disorders such as catamenial epilepsy (CE), postpartum depression (PPD) and premenstrual brain conditions. Neurosteroids are endogenous modulators of neuronal excitability. A variety of neurosteroids are present in the brain including allopregnanolone (AP), allotetrahydro‐deoxycorticosterone and androstanediol. Neurosteroids interact with synaptic and extrasynaptic GABAA receptors in the brain. AP and related neurosteroids, which are positive allosteric modulators of GABAA receptors, are powerful anticonvulsants, anxiolytic, antistress and neuroprotectant agents. In CE, seizures are most often clustered around a specific menstrual period in women. Neurosteroid withdrawal‐linked plasticity in extrasynaptic receptors has been shown to play a key role in catamenial seizures, anxiety and other mood disorders. Based on our extensive research spanning two decades, we have proposed and championed neurosteroid replacement therapy as a rational strategy for treating disorders marked by neurosteroid‐deficiency, such as CE and other related ovarian or menstrual disorders. In 2019, AP (renamed as brexanolone) was approved for treating PPD. A variety of synthetic neurosteroids are in clinical trials for epilepsy, depression and other brain disorders. Recent advancements in our understanding of neurosteroids have entered a new era of drug discovery and one that offers a high therapeutic potential for treating complex brain disorders.

show abstract

Molecular mechanisms of sex differences in epilepsy and seizure susceptibility in chemical, genetic and acquired epileptogenesis

Cited by 59 publications

References 131 publications

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions

Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women

Contact Info

Product

Resources

About