Repeated episodes of postictal hypoxia are a mechanism for interictal cognitive impairments.

Comorbidities during the period between seizures present a significant challenge for individuals with epilepsy. Despite their clinical relevance, the pathophysiology of the interictal symptomatology is largely unknown. Postictal severe hypoxia (PIH) in those brain regions participating in the seizure has been indicated as a mechanism underlying several negative postictal manifestations. It is unknown how repeated episodes of PIH affect interictal symptoms in epilepsy. Using a rat model, we observed that repeated seizures consistently induced episodes of PIH that become increasingly severe with each seizure occurrence. Additionally, recurrent seizure activity led to decreased levels of oxygen in the hippocampus during the interictal period. However, these reductions were prevented when we repeatedly blocked PIH using either the COX-inhibitor acetaminophen or the L-type calcium channel antagonist nifedipine. Moreover, we found that interictal cognitive deficits caused by seizures were completely alleviated by repeated attenuation of PIH events. Lastly, mitochondrial dysfunction may contribute to the observed pathological outcomes during the interictal period. These findings provide evidence that seizure-induced hypoxia may play a crucial role in several aspects of epilepsy. Consequently, developing and implementing treatments that specifically target and prevent PIH could potentially offer significant benefits for individuals with refractory epilepsy.

Paternal exposure to exercise and/or caffeine and alcohol modify offspring behavioral and pathophysiological recovery from repetitive mild traumatic brain injury in adolescence.

Only recently has the scope of parental research expanded to include the paternal sphere with epidemiological studies implicating stress, nutrition and alcohol consumption in the neurobiological and behavioral characteristics of offspring. This study was designed to determine if paternal exposure to caffeine, alcohol and exercise prior to conception would improve or exacerbate offspring recovery from adolescent repetitive mild traumatic brain injury (RmTBI). Sires received 7 weeks of standard drinking water, or caffeine and ethanol and were housed in regular cages or cages with running wheels, prior to being mated to control females. At postnatal day 40, offspring were administered RmTBI or sham injuries and were assessed for post concussive symptomology. Post-mortem quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess gene expression in the prefrontal cortex (PFC), nucleus accumbens (NAc) and changes in telomere length. Additionally, enzyme-linked immunosorbent assay (ELISA's) were run on serum to detect levels of cytokines, chemokines and sex hormones. Paternal experience did not improve or exacerbate RmTBI behavioral outcomes. However, female and male offspring displayed unique responses to RmTBI and paternal experience, resulting in changes in physical, behavioral and molecular outcomes. Injury and paternal exercise modified changes in female offspring, whereas male offspring were affected by paternal exercise, caffeine and alcohol treatment. Additionally, paternal experience and RmTBI modified expression of many genes in the PFC, NAc, telomere length and levels of sex hormones. Although further exploration is required to understand the heterogeneity that exists in disease risk and resiliency, this study provides corroborating evidence that paternal experiences prior to conception influences offspring development.

The ketogenic diet raises brain oxygen levels, attenuates postictal hypoxia, and protects against learning impairments.

OBJECTIVES: A prolonged vasoconstriction/hypoperfusion/hypoxic event follows self-terminating focal seizures. The ketogenic diet (KD) has demonstrated efficacy as a metabolic treatment for intractable epilepsy and other disorders but its effect on local brain oxygen levels is completely unknown. This study investigated the effects of the KD on tissue oxygenation in the hippocampus before and after electrically elicited (kindled) seizures and whether it could protect against a seizure-induced learning impairment. We also examined the effects of the ketone ß-hydroxybutyrate (BHB) as a potential underlying mechanism. METHODS: Male and female rats were given access to one of three diet protocols 2 weeks prior to the initiation of seizures: KD, caloric restricted standard chow, and ad libitum standard chow. Dorsal hippocampal oxygen levels were measured prior to initiation of diets as well as before and after a 10-day kindling paradigm. Male rats were then tested on a novel object recognition task to assess postictal learning impairments. In a separate cohort, BHB was administered 30 min prior to seizure elicitation to determine whether it influenced oxygen dynamics. RESULTS: The KD increased dorsal hippocampal oxygen levels, ameliorated postictal hypoxia, and prevented postictal learning impairments. Acute BHB administration did not alter oxygen levels before or after seizures. INTERPRETATION: The ketogenic diet raised brain oxygen levels and attenuated severe postictal hypoxia likely through a mechanism independent of ketosis and shows promise as a non-pharmacological treatment to prevent the postictal state.

Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats.

The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.

When Two Wrongs Make a Right: The Effect of Acute and Chronic Binge Drinking on Traumatic Brain Injury Outcomes in Young Adult Female Rats.

Alcohol is the most commonly abused drug by young adults across North America. Although alcohol consumption itself incurs a risk of neurological damage, it is also a significant risk factor for traumatic brain injury (TBI). TBI among young adults is described as a modern healthcare epidemic. The drastic changes occurring within their neurological networks put young adults at greater risk for developing long-term post-traumatic deficits. Contradictory findings have been indicated regarding the effects of alcohol consumption on TBI outcomes in adults, with some studies demonstrating detrimental effects, whereas others suggest neuroprotective abilities. However, little is known about the effects of alcohol consumption on TBI outcomes during the sensitive stage of early adulthood. Young adult female Sprague-Dawley rats were randomly assigned to one of six experimental conditions: Pre-injury alcohol+TBI; Pre-injury alcohol+Sham; Pre- and Post-injury alcohol+TBI; Pre- and Post-injury alcohol+Sham; No alcohol+TBI; No alcohol+Sham. Alcohol consumption groups received an amount of 10% v/v ethanol solution based on the animals' weight. Following the injury, the rats were subjected to a behavioral test battery to assess post-concussive symptomology. Overall, chronic binge drinking significantly improved TBI outcomes related to motor coordination and balance, whereas binge drinking in general significantly decreased anxiety-like behaviors. Additionally, in many cases, chronic binge drinking appears to return the TBI animal's behavioral outcomes to levels comparable to those of the no alcohol sham animals. Thus, the results suggest that alcohol may exhibit neuroprotective abilities in the context of early adulthood TBI.