Post-COVID seizure: A new feature of "long-COVID".

Novel coronavirus SARS-CoV-2 has created unprecedented healthcare challenges. Neurologic deficits are often an important presenting symptom. To date, the only reported post-infectious COVID-19 manifestations of neurologic disease include cognitive deficits and dysfunction of the peripheral nervous system. Here we report that seizure can also be a post-COVID-19 or "long-COVID" complication. We present a 71-year-old man with hypertension, diabetes mellitus, and COVID-19 diagnosed by RT-PCR who initially presented with posterior circulation stroke-like symptoms, which completely resolved after emergent thrombolysis. Six days later, the patient returned with seizure activity, supported by radiographic and electroencephalographic studies. Notably, he was negative for SARS-CoV-2, and no other provoking factor was uncovered after a comprehensive work-up. To our knowledge, this is the first report of post-infectious seizures after a case of COVID-19, highlighting the potential importance of monitoring for neurologic symptoms in COVID-19 patients, even after convalescence.

CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury.

Traumatic brain injury (TBI) induces secondary injury mechanisms, including cell cycle activation (CCA), that leads to neuronal death and neurological dysfunction. We recently reported that delayed administration of roscovitine, a relatively selective cyclin-dependent kinase (CDK) inhibitor, inhibits CCA and attenuates neurodegeneration and functional deficits following controlled cortical impact (CCI) injury in mice. Here we evaluated the neuroprotective potential of CR8, a more potent second-generation roscovitine analog, using the mouse CCI model. Key CCA markers (cyclin A and B1) were significantly up-regulated in the injured cortex following TBI, and phosphorylation of CDK substrates was increased. Central administration of CR8 after TBI, at a dose 20 times less than previously required for roscovitine, attenuated CCA pathways and reduced post-traumatic apoptotic cell death at 24 h post-TBI. Central administration of CR8, at 3 h after TBI, significantly attenuated sensorimotor and cognitive deficits, decreased lesion volume, and improved neuronal survival in the cortex and dentate gyrus. Moreover, unlike roscovitine treatment in the same model, CR8 also attenuated post-traumatic neurodegeneration in the CA3 region of the hippocampus and thalamus at 21 days. Furthermore, delayed systemic administration of CR8, at a dose 10 times less than previously required for roscovitine, significantly improved cognitive performance after CCI. These findings further demonstrate the neuroprotective potential of cell cycle inhibitors following experimental TBI. Given the increased potency and efficacy of CR8 as compared to earlier purine analog types of CDK inhibitors, this drug should be considered as a candidate for future clinical trials of TBI.

Cyclin D1 gene ablation confers neuroprotection in traumatic brain injury.

Cell cycle activation (CCA) is one of the principal secondary injury mechanisms following brain trauma, and it leads to neuronal cell death, microglial activation, and neurological dysfunction. Cyclin D1 (CD1) is a key modulator of CCA and is upregulated in neurons and microglia following traumatic brain injury (TBI). In this study we subjected CD1-wild-type (CD1(+/+)) and knockout (CD1(-/-)) mice to controlled cortical impact (CCI) injury to evaluate the role of CD1 in post-traumatic neurodegeneration and neuroinflammation. As early as 24 h post-injury, CD1(+/+) mice showed markers of CCA in the injured hemisphere, including increased CD1, E2F1, and proliferating cell nuclear antigen (PCNA), as well as increased Fluoro-Jade B staining, indicating neuronal degeneration. Progressive neuronal loss in the hippocampus was observed through 21 days post-injury in these mice, which correlated with a decline in cognitive function. Microglial activation in the injured hemisphere peaked at 7 days post-injury, with sustained increases at 21 days. In contrast, CD1(-/-) mice showed reduced CCA and neurodegeneration at 24 h, as well as improved cognitive function, attenuated hippocampal neuronal cell loss, decreased lesion volume, and cortical microglial activation at 21 days post-injury. These findings indicate that CD1-dependent CCA plays a significant role in the neuroinflammation, progressive neurodegeneration, and related neurological dysfunction resulting from TBI. Our results further substantiate the proposed role of CCA in post-traumatic secondary injury, and suggest that inhibition of CD1 may be a key therapeutic target for TBI.