Exacerbation Of Neurological Deficits Research Articles

TREM2 deficiency impairs the energy metabolism of Schwann cells and exacerbates peripheral neurological deficits

Triggering receptor expressed on myeloid cells-2 (TREM2) has been implicated in susceptibility to neurodegenerative disease. Schwann cells (SCs), the predominant glial cell type in the peripheral nervous system (PNS), play a crucial role in myelination, providing trophic support for neurons and nerve regeneration. However, the function of TREM2 in SCs has not been fully elucidated. Here, we found that TREM2 is expressed in SCs but not in neurons in the PNS. TREM2 deficiency leads to disruption of glycolytic flux and oxidative metabolism in SCs, impairing cell proliferation. The energy crisis caused by TREM2 deficiency triggers mitochondrial damage and autophagy by activating AMPK and impairing PI3K-AKT-mTOR signaling. Combined metabolomic analysis demonstrated that energic substrates and energy metabolic pathways were significantly impaired in TREM2-deficient SCs. Moreover, TREM2 deficiency impairs energy metabolism and axonal growth in sciatic nerve, accompanied by exacerbation of neurological deficits and suppression of nerve regeneration in a mouse model of acute motor axonal neuropathy. These results indicate that TREM2 is a critical regulator of energy metabolism in SCs and exerts neuroprotective effects on peripheral neuropathy.TREM2 deficiency impairs glycolysis and oxidative metabolism in Schwann cells, resulting in compromised cell proliferation. The energy crisis caused by TREM2 deficiency induces mitochondrial damage and autophagy by activating AMPK and impairing PI3K-AKT-mTOR signaling. Moreover, TREM2 deficiency disrupts the energy metabolism of the sciatic nerve and impairs support for axonal regeneration, accompanied by exacerbation of neurological deficits and suppression of nerve regeneration in a mouse model of acute motor axonal neuropathy (by FigDraw).

Inhibition of Mer exacerbates early brain injury by regulating microglia/macrophage phenotype after subarachnoid hemorrhage in mice

BackgroundPolarization of microglia/macrophages toward the pro-inflammatory phenotype is a crucial contributor to neuroinflammation after subarachnoid hemorrhage (SAH). Mer belongs to the TAM receptor tyrosine kinases family, which is known to play a significant role in the resolution of inflammation. However, the effect and mechanism of Mer after SAH remain unclear. In this study, we explored the effect of Mer on modulating the microglia/macrophage phenotype and neuroinflammation and possible potential mechanism after SAH. Method: Endovascular perforation model of SAH was performed. There are 3 parts in this study. Firstly, the time course of Mer expression was determined within 72 hours after SAH. Secondly, the effect of Mer downregulation on brain water content, neurological function, and microglial polarization was evaluated at 24 h after SAH. Thirdly, the neuroprotective effects of pharmacological Mer agonist were assessed. Result: The expression of Mer increased after SAH, and was prominently localized in microglia/macrophages. Treatment with Mer siRNA increased pro-inflammatory phenotype and decreased anti-inflammatory phenotype of microglia/macrophage, thus resulted in exacerbation of neurological deficits and brain edema after SAH. Mechanistically, the downregulation of Mer inhibited the downstream anti-inflammatory signals, SOCS1/SOCS3, by decreasing phosphorylated STATs. Conclusion: Mer is involved in the microglia/macrophage polarization and inflammation resolution after SAH, and that mechanism, at least in part, may contribute to the involvement of the STATs/SOCSs pathway.

Abstract 110: RNA Sequencing Reveals Novel Macrophage Transcriptome Favoring Neurovascular Plasticity After Ischemic Stroke

Introduction: Blood monocytes/macrophages (MΦ) infiltrate the brain in massive numbers after ischemic stroke, but their functional roles in the post-stroke brain remain elusive. Methods: We sorted CD11b + CD45 high monocytes/MΦ from mouse blood and brain 5d after distal MCAO (dMCAO) and investigated their transcriptomic profiles by RNA-seq (n=3/group). Results: Robust genomic changes occurred in MΦ invading the post-dMCAO brain compared to their counterparts in the blood (3196 differentially expressed genes with >2 fold changes; FDR<0.05). In addition to their canonical role in immune responses, brain MΦ expressed unique transcriptomic programs which may favor post-stroke neurovascular repair. Functional enrichment analysis of brain MΦ transcriptome revealed significant overrepresentation (p<0.01) of 110 biological processes linked to neurovascular remodeling and plasticity (e.g., angiogenesis and axonal regeneration), suggesting a previously underappreciated role for MΦ in post-stroke brain repair. Upstream Regulator analysis predicted PPARγ as a master regulator (z-score=2.64, p<10 -15 ) that drives the transcriptional reprogramming in post-stroke brain MΦ and dictates their functional phenotype. Accordingly, tamoxifen-induced, myeloid cell-specific PPARγ knockout mice demonstrated less post-stroke angiogenesis (BrdU+CD31 staining) and neurogenesis (BrdU+NeuN) than WT mice (n=9/group, p<0.01), which correlated significantly with the exacerbation of neurological deficits in these mice (n=9/group, p<0.01 vs WT in foot fault and adhesive removal tests) at 35d after dMCAO. Conclusions: Our study reveals a novel repair-enhancing transcriptome in brain MΦ during post-stroke neurovascular remodeling. As a master molecule controlling genomic reprogramming, PPARγ is a rational therapeutic target for promoting beneficial MΦ functions, and facilitating neurorestoration and long term functional recovery after ischemic stroke.

The use of functional magnetic resonance imaging in reducing a risk of postoperative neurological deficits in the patients with brain tumour

Background and purposeThe purpose of the study was to compare the results of operative treatment of tumours located in the sensory-motor cortex guided with functional magnetic resonance imaging (fMRI) combined with the neuronavigation system to the results of classical operative treatment. Material and methodsThe studied group comprised 28 patients with a tumour located in the sensory-motor cortex area who underwent surgery guided with fMRI and the neuronavigation system. A control group comprised 30 patients with the same clinical diagnosis, operated on without functional neuronavigation. ResultsThe use of functional neuronavigation allowed for an 18% reduction in the intensity of neurological deficits after surgical treatment in patients from the studied group, compared to the subjects from the control group (p = 0.0001). In the patients with diagnosed high-grade glioma, improvement in the neurological condition in the studied group was 16% (p = 0.03). The initial neurological condition and the results of surgical treatment in patients with a tumour located less than 5 mm from the sensory-motor cortex, determined in fMRI examination, are worse than in patients with a tumour located more than 5 mm. ConclusionsIn patients with a diagnosed brain tumour in the sensory-motor cortex who have neurological deficits, fMRI provides valuable imaging data on active areas. Tumour location of more than 5 mm from the fMRI active area of the sensory-motor cortex is connected with a considerably lower risk of postoperative neurological deficits. Removing a tumour in the sensory-motor cortex region, guided with fMRI and the neuronavigation system, considerably lowers the risk of postoperative development or exacerbation of neurological deficits.

Intramedullary spinal cord germinoma—2 case reports

Background Primary intramedullary spinal cord germinoma is very rare. We encountered 2 patients with primary intramedullary spinal cord germinoma. We describe herein our comprehensive management system for CNS germinoma, including intramedullary spinal cord germinoma, along with a review of the literature. This is the first report to describe successful application of ICE chemotherapy for intramedullary germinoma. Case Descriptions A 16-year-old adolescent girl (case 1) experienced lumbago and subsequently noticed gait disturbance that aggravated gradually. On admission, paraparesis and urinary retention were noted. Magnetic resonance imaging demonstrated marked cord swelling between T9 and T12, with slight enhancement in the spinal cord. Astrocytic tumor was initially suspected, and partial removal was performed. However, pathologic examination identified germinoma. Successful treatment with ICE chemotherapy and radiotherapy was implemented, with no evidence of recurrence apparent at 48 months postoperatively. A 34-year-old woman (case 2) presented with paraparesis and sensory disturbance. Magnetic resonance imaging demonstrated cord swelling between T8 and T10, with slight Gd-DTPA enhancement. Because the lesion did not respond to steroid pulse therapy, spinal cord tumor was suspected and biopsy was performed. Pathologic examination verified primary germinoma of the spine. Successful treatment with ICE chemotherapy and radiotherapy was implemented with no exacerbation of neurologic deficits. No evidence of recurrence was apparent at 36 months postoperatively. Conclusion Correct diagnosis of very rare primary intramedullary spinal cord germinoma is important, because these patients can be treated successfully using chemo- and radiotherapy without neurologic deterioration.

Recurrent intraparenchymal hemorrhages from angiographically occult vascular malformations

Thirteen patients with recurrent hemorrhages from angiographically occult vascular malformations are presented. Recurrent hemorrhages were indicated by the exacerbation of neurological deficits, the appearance of a new neurological deficit, or the onset of acute severe headache confirmed by evidence of recent hemorrhage on either computerized tomography or magnetic resonance imaging. Persistent neurological deficits correlated with an increased number of recurrent hemorrhages and their location. The median time from initial hemorrhage to the first recurrent hemorrhage was 12 months and the second rebleed generally occurred much earlier, with a median time of 2 months after the first. Eight patients underwent surgery with total excision and favorable results. One patient with a large pontine lesion underwent partial excision and has had a progressing neurological deficit from recurrent hemorrhages. Histopathological review confirmed the excised lesions to be cavernous angiomas. The authors conclude that angiographically occult vascular malformations are not the benign entity they were previously thought to be, and that they are prone to cause recurrent hemorrhages and persistent neurological deficits. Surgery can be effective and relatively safe in removing these lesions even in eloquent areas of the brain, but the necessity of occasional incomplete removal must be recognized in order to avoid creating an unacceptable neurological outcome.

Naloxone and mortality in the gerbil stroke model.

Endorphins and narcotics have been implicated in the exacerbation of neurologic deficits after stroke. To test the theory that narcotic antagonists might offer an improvement in neurologic sequelae following stroke, we administered various doses of naloxone intraperitoneally to 50 adult gerbils 45 minutes after carotid artery transsection. Low-dose naloxone therapy (1.0 to 2.5 mg/kg) was more effective in preventing death than either control (sterile saline) or high-dose naloxone (10 mg/kg). A naloxone dose of 1.0 or 2.5 mg/kg offered a significant improvement in mortality over both the control and the high-dose therapy (P = .026). It appears that an appropriate dose of naloxone (1.0 to 2.5 mg/kg), given early enough to alter outcome, offers an improved survival in the gerbil stroke model. This finding obviously has significant implications for the use of narcotic antagonists in human beings with stroke.