Electroacupuncture promotes remyelination and alleviates cognitive deficit via promoting OPC differentiation in a rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating cerebral vascular disease which causes neurological deficits including long-term cognitive deficit. Demyelination of white matter is correlated with cognitive deficit in SAH. Electroacupuncture (EA) is a traditional Chinese medical treatment which protects against cognitive deficit in varies of neurological diseases. However, whether EA exerts protective effect on cognitive function in SAH has not been investigated. The underlying mechanism of remyelination regulated by EA remains unclear. This study aimed to investigate the protective effects of EA on cognitive deficit in a rat model of SAH. SAH was induced in SD rats (n = 72) by endovascular perforation. Rats in EA group received EA treatment (10 min per day) under isoflurane anesthesia after SAH. Rats in SAH and sham groups received the same isoflurane anesthesia with no treatment. The mortality rate, neurological score, cognitive function, cerebral blood flow (CBF), and remyelination in sham, SAH and EA groups were assessed at 21 d after SAH.EA treatment alleviated cognitive deficits and myelin injury of rats compared with that in SAH group. Moreover, EA treatment enhanced remyelination in white matter and promoted the differentiation of OPCs after SAH. EA treatment inhibited the expression of Id2 and promoted the expression of SOX10 in oligodendrocyte cells. Additionally, the cerebral blood flow (CBF) of rats was increased by EA compared with that in SAH group. EA treatment exerts protective effect against cognitive deficit in the late phase of SAH. The underlying mechanisms involve promoting oligodendrocyte progenitor cell (OPC) differentiation and remyelination in white matter via regulating the expression of Id2 and SOX10. The improvement of CBF may also account for the protective effect of EA on cognitive function. EA treatment is a potential therapy for the treatment of cognitive deficit after SAH.

MCC950 ameliorates cognitive function by reducing white matter microstructure damage in rats after SAH.

Neuroinflammation and white matter microstructure damage are important causes of cognitive impairment after subarachnoid hemorrhage (SAH). Nod-like receptor protein 3 (NLRP3) plays an important role in neuroinflammation after SAH and may be a potential therapeutic target for treatment of white matter microstructure injury. In this study, we observed whether MCC950, a specific inhibitor of the NLRP3 inflammasome, exerted a therapeutic effect after SAH. The SAH model was induced by endovascular perforation in SpragueDawley rats. MCC950 was injected intraperitoneally 1 h after SAH at a dose of 10 mg/kg. The results showed that MCC950 significantly attenuated white matter microstructure damage in some brain regions, and behavioral experiments confirmed that MCC950 ameliorated cognitive function in rats after SAH, which may provide a new method for the treatment of cognitive dysfunction in SAH patients.

The Association of LDH Expression and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: Possible Involvement of Cerebral Blood Perfusion.

BACKGROUND AND PURPOSE: Several pieces of evidence suggest that serum lactate hydrogenase (LDH) level is associated with the pathological process of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). This research aimed to investigate the associations of serum LDH level with the occurrence of DCI in aSAH patients. METHODS: A total of 122 patients diagnosed with aSAH within 72h of onset were retrospectively enrolled. The serum levels of LDH between 7:00-8:00 am on day 1, day 3 and day 7, patients' demographics, and clinical features were collected. Computed tomography perfusion was performed within 7 days after aSAH. The occurrence of DCI was recorded during the hospitalization. RESULTS: Among all the enrolled patients, 43 (35.2%) developed DCI during hospitalization. Patients occurred DCI were always accompanied by more serious clinical features and found with higher serum LDH levels. LDH levels on day 3 and day 7 after onset were independently associated with the occurrence of DCI and showed high predictive value according to the receiver operating characteristic (ROC) curve. Moreover, there was a strong correlation between LDH and mean cerebral blood flow, transit time, and mean time to peak. CONCLUSION: Serum LDH level on day 3 and day 7 may be a valuable, convenient, and rapid predictive indicator for the occurrence of DCI in aSAH patients.

Electroacupuncture alleviates early brain injury via modulating microglia polarization and suppressing neuroinflammation in a rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage refers to an uncommon but severe subtype of stroke leading to high mortality and disability rates. Electroacupuncture, a traditional Chinese medical therapy combined with modern technology, shows evident curative effects on cerebral vascular diseases. This study attempts to investigate the possible treatment effects and mechanisms of EA on early brain injury after SAH. Data were gathered among sham group, SAH-induced group, and EA-treated group of male SD rats, concerning mortality rates, weight loss, rotarod latencies, cerebral blood flow, cell apoptosis, pro-inflammatory cytokines releasing, apoptotic protein level, microglia activation and related signal pathway. All results were collected 24-72 h after SAH induction. EA treatment demonstrated significant improvement on motor function 24 h after SAH without significant changes in mortality rate, weight loss, and cerebral blood flow. Another important finding was that EA regulated Bax and Bcl-2 imbalance and reduced cleaved casepase-3 caused by SAH. Additionally, levels of TNF-α, IL-1ß, IL-6 were suppressed. The neuron apoptosis was suppressed by EA. The M1 polarization of activated microglia decreased while M2 polarized phenotype increased after EA treatment. Furthermore, pSTAT3-NOX2 signal axis, the M1 phenotype related activation pathway, was depressed after EA treatment. These findings suggested that EA improved motor deficits and ameliorated early brain injury after SAH probably via decreasing neuron apoptosis and anti-inflammation, which may involve modulation of microglia polarization. Taken together, EA may be a potential therapy for SAH treatment.

Selective sphingosine-1-phosphate receptor 1 modulator attenuates blood-brain barrier disruption following traumatic brain injury by inhibiting vesicular transcytosis.

BACKGROUND: Traumatic brain injury (TBI) provokes secondary pathological damage, such as damage to the blood-brain barrier (BBB), ischaemia and inflammation. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be critical in limiting the increase in BBB vesicle transcytosis following brain injury. Recent studies suggest that a novel and selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1), CYM-5442, maintains the integrity of the BBB by restricting vesicle transcytosis during acute ischaemic stroke. In the current study, we investigated whether CYM-5442, evaluated in a short-term study, could protect the brains of mice with acute-stage TBI by reversing the increase in vesicle transport due to reduced Mfsd2a expression after TBI. METHODS: We used the well-characterized model of TBI caused by controlled cortical impact. CYM-5442 (0.3, 1, 3 mg/kg) was intraperitoneally injected 30 min after surgery for 7 consecutive days. To investigate the effect of CYM-5442 on vesicle transcytosis, we downregulated and upregulated Mfsd2a expression using a specific AAV prior to evaluation of the TBI model. MRI scanning, cerebral blood flow, circulating blood counts, ELISA, TEM, WB, and immunostaining evaluations were performed after brain injury. RESULTS: CYM-5442 significantly attenuated neurological deficits and reduced brain oedema in TBI mice. CYM-5442 transiently suppressed lymphocyte trafficking but did not induce persistent lymphocytopenia. After TBI, the levels of Mfsd2a were decreased significantly, while the levels of CAV-1 and albumin were increased. In addition, Mfsd2a deficiency caused inadequate sphingosine-1-phosphate (S1P) transport in the brain parenchyma, and the regulation of BBB permeability by Mfsd2a after TBI was shown to be related to changes in vesicle transcytosis. Downregulation of Mfsd2a in mice markedly increased the BBB permeability, neurological deficit scores, and brain water contents after TBI. Intervention with CYM-5442 after TBI protected the BBB by significantly reducing the vesicle transcytosis of cerebrovascular endothelial cells. CONCLUSION: In addition to transiently suppressing lymphocytes, CYM-5442 alleviated the neurological deficits, cerebral edema and protective BBB permeability in TBI mice by reducing the vesicle transcytosis of cerebrovascular endothelial cells.