PRMT7 can prevent neurovascular uncoupling, blood-brain barrier permeability, and mitochondrial dysfunction in repetitive and mild traumatic brain injury.

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI.

A role for protein arginine methyltransferase 7 in repetitive and mild traumatic brain injury.

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky's silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro.

Early mobilization versus bed rest for incidental durotomy: an institutional cohort study.

OBJECTIVE: The aim of this study was to assess whether flat bed rest for > 24 hours after an incidental durotomy improves patient outcome or is a risk factor for medical and wound complications and longer hospital stay. METHODS: Medical records of consecutive patients undergoing thoracic and lumbar decompression procedures from 2010 to 2020 were reviewed. Operative notes and progress notes were reviewed and searched to identify patients in whom incidental durotomies occurred. The need for revision surgery related to CSF leak or wound infection was recorded. The duration of bed rest, length of hospital stay, and complications (pulmonary, gastrointestinal, urinary, and wound) were recorded. The rates of complications were compared with regard to the duration of bed rest (≤ 24 hours vs > 24 hours). RESULTS: A total of 420 incidental durotomies were identified, indicating a rate of 6.7% in the patient population. Of the 420 patients, 361 underwent primary repair of the dura; 254 patients were prescribed bed rest ≤ 24 hours, and 107 patients were prescribed bed rest > 24 hours. There was no statistically significant difference in the need for revision surgery (7.87% vs 8.41%, p = 0.86) between the two groups, but wound complications were increased in the prolonged bed rest group (8.66% vs 15.89%, p = 0.043). The average length of stay for patients with bed rest ≤ 24 hours was 4.47 ± 3.64 days versus 7.24 ± 4.23 days for patients with bed rest > 24 hours (p < 0.0001). There was a statistically significant increase in the frequency of ileus, urinary retention, urinary tract infections, pulmonary issues, and altered mental status in the group with prolonged bed rest after an incidental durotomy. The relative risk of complications in the group with bed rest ≤ 24 hours was 50% less than the group with > 24 hours of bed rest (RR 0.5, 95% CI 0.39-0.62; p < 0.0001). CONCLUSIONS: In this retrospective study, the rate of revision surgery was not higher in patients with durotomy who underwent immediate mobilization, and medical complications were significantly decreased. Flat bed rest > 24 hours following incidental durotomy was associated with increased length of stay and increased rate of medical complications. After primary repair of an incidental durotomy, flat bed rest may not be necessary and appears to be associated with higher costs and complications.