The LPA-CDK5-tau pathway mediates neuronal injury in an in vitro model of ischemia-reperfusion insult.

Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

Neurocognitive improvement after angioplasty in patients with chronic middle cerebral artery stenosis and cerebral ischemia.

BACKGROUND: The use of middle cerebral artery (MCA) angioplasty compared with drug therapy has been controversial. Few studies have reported the correlations between cognitive function improvement and MCA angioplasty. This study aimed to explore neurocognitive function after angioplasty in patients with middle cerebral artery stenosis (MCAS) and objective cerebral ischemia. METHODS: We identified 14 patients diagnosed with MCAS aged 45-65 years. Neurocognitive function evaluation was performed by 2 independent clinical psychologists using the Mini-Mental State Examination (MMSE), Montreal cognitive assessment scale (MoCA), and Multi-Dimensional Psychology. All patients received general anesthesia, underwent diagnostic cerebral angiography (DSA) via the femoral route and angioplasty, and then were sent to the neurologic intensive care unit (NICU) for overnight hemodynamic and neurologic monitoring. Aspirin and clopidogrel treatments were continued for 3 months after successful intervention. Complete neurologic examinations, including assessment with the National Institutes of Health Stroke (NIHSS), and modulate RANK score (MRS) were conducted by 2 independent neurologists. The patients received a family follow-up at 1 week, 1 month, and 3 months after the interventional procedure. Neurologic sequelae, intracranial hemorrhages, and deaths were recorded as an endpoint. Follow-up clinical and imageological examinations were scheduled at 6 months after the intervention. Follow-up brain computed tomography (CT) perfusion or magnetic resonance angiography (MRA) perfusion scans performed by 2 imageological scanners were scheduled 6 months after the procedure. RESULTS: Angioplasty technical success was achieved in 14 parents (100%). We found that 10 patients did not have recurrent MCAS in the angioplasty site and had significant improvements in the associated brain perfusion situation and cognitive founction as compared before and after angioplasty. Also, 4 patients had evident restenosis in the angioplasty site. In the nonstenosis group, we found significant improvements in the MMSE, 3-dimensional (3D) mental rotation, simple calculation, and spatial working memory. In the recurrent stenosis group, we found no statistically significant changes in cognitive function compared with the baseline and after a 6-month follow up. There were high correlations between the changes in perfusion and the changes in word and picture memory. There was a significant correlation between the change in perfusion with MMSE (-0.522), spatial working memory (0.655), and Raven's progressive matrices test (0.637); a moderate correlation with 3D rotation (0.413), and simple calculation (-0.359); and weak correlation with visual tracking (0.026) and MoCA (0.279). CONCLUSIONS: Angioplasty surgery significantly improves neurocognitive function in patients with middle cerebral artery stenosis (MCAS) and objective cerebral ischemia.