Anti-seizure medication-induced developmental cell death in neonatal rats is unaltered by history of hypoxia.

BACKGROUND: Many anti-seizure medications (ASMs) trigger neuronal cell death when administered during a confined period of early life in rodents. Prototypical ASMs used to treat early-life seizures such as phenobarbital induce this effect, whereas levetiracetam does not. However, most prior studies have examined the effect of ASMs in naïve animals, and the degree to which underlying brain injury interacts with these drugs to modify cell death is poorly studied. Moreover, the degree to which drug-induced neuronal cell death differs as a function of sex is unknown. METHODS: We treated postnatal day 7 Sprague Dawley rat pups with vehicle, phenobarbital (75 mg/kg) or levetiracetam (200 mg/kg). Separate groups of pups were pre-exposed to either normoxia or graded global hypoxia. Separate groups of males and females were used. Twenty-four hours after drug treatment, brains were collected and processed for markers of cell death. RESULTS: Consistent with prior studies, phenobarbital, but not levetiracetam, increased cell death in cortical regions, basal ganglia, hippocampus, septum, and lateral thalamus. Hypoxia did not modify basal levels of cell death. Females - collapsed across treatment and hypoxia status, displayed a small but significant increase in cell death as compared to males in the cingulate cortex, somatosensory cortex, and the CA1 and CA3 hippocampus; these effects were not modulated by hypoxia or drug treatment. CONCLUSION: We found that a history of graded global hypoxia does not alter the neurotoxic profile of phenobarbital. Levetiracetam, which does not induce cell death in normal developing animals, maintained a benign profile on the background of neonatal hypoxia. We found a sex-based difference, as female animals showed elevated levels of cell death across all treatment conditions. Together, these data address several long-standing gaps in our understanding of the neurotoxic profile of antiseizure medications during early postnatal development.

Phenobarbital does not worsen outcomes of neonatal hypoxia on hippocampal LTP on rats.

Introduction: Neonatal hypoxia is a common cause of early-life seizures. Both hypoxia-induced seizures (HS), and the drugs used to treat them (e.g., phenobarbital, PB), have been reported to have long-lasting impacts on brain development. For example, in neonatal rodents, HS reduces hippocampal long-term potentiation (LTP), while PB exposure disrupts GABAergic synaptic maturation in the hippocampus. Prior studies have examined the impact of HS and drug treatment separately, but in the clinic, PB is unlikely to be given to neonates without seizures, and neonates with seizures are very likely to receive PB. To address this gap, we assessed the combined and separate impacts of neonatal HS and PB treatment on the development of hippocampal LTP. Methods: Male and female postnatal day (P)7 rat pups were subjected to graded global hypoxia (or normoxia as a control) and treated with either PB (or vehicle as a control). On P13-14 (P13+) or P29-37 (P29+), we recorded LTP of the Schaffer collaterals into CA1 pyramidal layer in acute hippocampal slices. We compared responses to theta burst stimulation (TBS) and tetanization induction protocols. Results: Under the TBS induction protocol, female rats showed an LTP impairment caused by HS, which appeared only at P29+. This impairment was delayed compared to male rats. While LTP in HS males was impaired at P13+, it normalized by P29+. Under the tetanization protocol, hypoxia produced larger LTP in males compared to female rats. PB injection, under TBS, did not exacerbate the effects of hypoxia. However, with the tetanization protocol, PB - on the background of HS - compensated for these effects, returning LTP to control levels. Discussion: These results point to different susceptibility to hypoxia as a function of sex and age, and a non-detrimental effect of PB when administered after hypoxic seizures.

Optogenetic activation of the superior colliculus attenuates spontaneous seizures in the pilocarpine model of temporal lobe epilepsy.

OBJECTIVE: Decades of studies have indicated that activation of the deep and intermediate layers of the superior colliculus can suppress seizures in a wide range of experimental models of epilepsy. However, prior studies have not examined efficacy against spontaneous limbic seizures. The present study aimed to address this gap through chronic optogenetic activation of the superior colliculus in the pilocarpine model of temporal lobe epilepsy. METHODS: Sprague Dawley rats underwent pilocarpine-induced status epilepticus and were maintained until the onset of spontaneous seizures. Virus coding for channelrhodopsin-2 was injected into the deep and intermediate layers of the superior colliculus, and animals were implanted with head-mounted light-emitting diodes at the same site. Rats were stimulated with either 5- or 100-Hz light delivery. Seizure number, seizure duration, 24-h seizure burden, and behavioral seizure severity were monitored. RESULTS: Both 5- and 100-Hz optogenetic stimulation of the deep and intermediate layers of the superior colliculus reduced daily seizure number and total seizure burden in all animals in the active vector group. Stimulation did not affect either seizure duration or behavioral seizure severity. Stimulation was without effect in opsin-negative control animals. SIGNIFICANCE: Activation of the deep and intermediate layers of the superior colliculus reduces both the number of seizures and total daily seizure burden in the pilocarpine model of temporal lobe epilepsy. These novel data demonstrating an effect against chronic experimental seizures complement a long history of studies documenting the antiseizure efficacy of superior colliculus activation in a range of acute seizure models.

Prevalence and Correlates of Depressive Symptoms Within 6 Months After First-Time Mild Traumatic Brain Injury.

OBJECTIVE: Depressive symptoms are among the most common neuropsychiatric sequelae of mild traumatic brain injury (mTBI). Very few studies have compared correlates of depressive symptoms within the first 6 months of injury in cohorts experiencing their first TBI. The authors investigated whether the correlates of depressive symptoms (being female, older, lower education, having brain lesions, experiencing worse postconcussive symptoms, and incomplete functional recovery) that have been established in populations with moderate to severe TBI were the same for individuals with first-time mTBI within the first 6 months of recovery. METHODS: Two hundred seventeen individuals with first-time mTBI were divided into subgroups-new-onset depressive symptoms, recurrent depressive symptoms, prior depression history only, and never depressed-and compared on clinical and demographic variables and the presence of postconcussive symptoms and functional recovery at 3 and 6 months. RESULTS: New-onset depressive symptoms developed in 12% of the cohort, whereas 11% of the cohort had recurrent depressive symptoms. Both depressive symptoms groups were more likely to comprise women and persons of color and were at higher risk for clinically significant postconcussive symptoms and incomplete functional recovery for the first 6 months postinjury. CONCLUSIONS: Presence of depressive symptoms after first-time mTBI was associated with persistent postconcussive symptoms and incomplete functional recovery in the first 6 months. Adding to the existing literature, these findings identified correlates of depressive symptom development and poor outcomes after mTBI, thus providing further evidence that mTBI may produce persistent symptoms and functional limitations that warrant clinical attention.