Berberine protects against chronic cerebral hypoperfusion-induced cognitive impairment and hippocampal damage via regulation of the ERK/Nrf2 pathway.

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood-brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.

The Chinese herb Fructus Broussonetiae aids learning and memory in chronic cerebral hypoperfusion by reducing proinflammatory microglia activation in rats.

The neuroprotective role of Fructus Broussonetiae in a model of chronic cerebral hypoperfusion with cognitive decline was focused on neural plasticity and microglia/macrophage polarization. Chronic cerebral hypoperfusion was induced by bilateral common carotid artery ligation. Fructus Broussonetiae shortened escape latency and added the number of platform crossings of rats, up-regulated the expression of synaptophysin in the gray matter and increased myelin basic protein expression in the white matter. Further mechanistic experiments were conducted to examine microglia activation and M1/M2 polarization. It was shown that Fructus Broussonetiae reduced the activation of microglia revealed by decreased expression of ionized calcium-binding adapter molecule-1, inhibited M1 polarization of microglia and improved microglial M2 polarization shown by down-regulated the expression of inducible nitric oxide synthase and Fc fragment of IgG receptor IIIa and up-regulated the expression of arginase-1. In conclusion, the Chinese herb Fructus Broussonetiae can improve cognitive function following chronic cerebral hypoperfusion by down-regulating the activation of microglia, inhibiting microglial M1 polarization, and improving neural plasticity.

Huoluo Yinao decoction mitigates cognitive impairments after chronic cerebral hypoperfusion in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Huoluo Yinao decoction (HLYND) has been used to ameliorate cognitive impairment induced by chronic cerebral hypoperfusion in clinical for years. However, the exact mechanisms remain unknown. AIM OF THE STUDY: To investigate the effects and mechanisms underlying HLYND-mediated improvement in cognitive deficits associated with chronic cerebral hypoperfusion. MATERIALS AND METHODS: Thirty-six Sprague-Dawley rats were randomly allocated to three groups: sham, model, and HLYND. Daily administration of HLYND or volume-matched vehicle by gavage was initiated 1 day after bilateral carotid artery stenosis (BCAS) and continued for 42 days. The Morris water maze (MWM) test was used to assess cognitive functions from days 36-42. Via western blot and immunofluorescent staining, restoration of neuronal plasticity and remyelination of white matter were evaluated by analyzing the expression profiles of MAP-2, synaptophysin and MBP. In addition, macrophage/microglial activation was assessed by quantifying changes in Iba1, and macrophage/microglial polarization was assessed by changes in iNOS and CD16 (M1 markers), as well as Arg1 and CD206 (M2 markers). RESULTS: In the MWM test, BCAS rats showed significantly extended escape latency and reduced platform crossing times, while those in the HLYND group had shortened escape latency and increased frequency of platform crossing. In addition, rats in the model group showed decreased levels and abnormal morphological changes of MAP-2, synaptophysin and MBP, whereas HLYND administration reversed these effects. As expected, Iba1 levels were elevated in both the model and HLYND groups but rats in the model group showed increased levels of the M1 markers, iNOS and CD16, and a correspondent decrease in the M2 marker, Arg1. In contrast, in the HLYND group, iNOS and CD16 levels were suppressed, while Arg1 levels were elevated. CONCLUSIONS: Our findings demonstrate that HLYND mitigates cognitive impairment after chronic cerebral hypoperfusion in rats through mechanisms involving increased neuronal plasticity and white matter remyelination, with a subtile modulation of macrophage/microglial polarization toward the M2 phenotype.

Xuesaitong May Protect Against Ischemic Stroke by Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis via the STAT3 Signaling Pathway.

BACKGROUND: Xuesaitong mainly comprises Panax notoginseng saponins and has shown a promising feature in an acute ischemic stroke model; however, its effect on long-term recovery following stroke, and the related mechanisms, are unknown. METHODS: The objective of this study was to investigate the long-term protective effects of xuesaitong against ischemic stroke and its effect on microglial polarization. Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 45 min, and C57BL/6 mice were immediately injected with xuesaitong or vehicle through the caudal vein at the onset of cerebral reperfusion consecutively for 14 days. The animals were randomly divided into three groups: a sham-operated group, vehicle-treated group and xuesaitong-treated group at a dose of 15µg/g. Subsequently, 2,3,5-triphenyltetrazolium chloride staining was used to assess infarct volume, and adhesive removal tests and balance beam tests were used to evaluate neurological deficits at days 1, 3, 7 and 14 following ischemia. Reverse-transcriptase polymerase chain reaction and immunofluorescence staining for M1 markers (CD16, iNOS) and M2 markers (CD206, arginase-1) were performed to characterize phenotypic changes in microglia. Elisa was used to determine the release of pro-inflammatory and anti-inflammatory cytokines. TUNEL staining was conducted to detect neuronal cell apoptosis, and western blots were used to determine the activation of signal transducer and activator of transcription 3 (STAT3). RESULTS: Our results revealed that xuesaitong treatment, compared with vehicle treatment, significantly reduced cerebral infarct volume 1 and 3 days after MCAO and resulted in significant improvements in long-term neurological outcomes. Furthermore, xuesaitong treatment, compared with vehicle treatment, significantly reduced M1 markers and elevated M2 markers 7 and 14 days after MCAO at both the mRNA and protein level in ipsilateral brain tissue. This finding was also accompanied by a reduction in neuronal cell apoptosis and p-STAT3 transcription factor levels in the xuesaitong-treated group compared with the vehicle-treated group. CONCLUSION: We demonstrated that xuesaitong has long-term neuroprotective effects against ischemic stroke, possibly by promoting the polarization of microglia to an M2 phenotype and by inhibiting neuronal cell death via down-regulation of the STAT3 signaling pathway, providing new evidence that xuesaitong might be a promising therapeutic strategy for ischemic stroke.

Luoyutong Treatment Promotes Functional Recovery and Neuronal Plasticity after Cerebral Ischemia-Reperfusion Injury in Rats.

Luoyutong (LYT) capsule has been used to treat cerebrovascular diseases clinically in China and is now patented and approved by the State Food and Drug Administration. In this retrospective validation study we investigated the ability of LYT to protect against cerebral ischemia-reperfusion injury in rats. Cerebral ischemia-reperfusion injury was induced by middle cerebral artery occlusion followed by reperfusion. Capsule containing LYT (high dose and medium dose) as treatment group and Citicoline Sodium as positive control treatment group were administered daily to rats 30 min after reperfusion. Treatment was continued for either 3 days or 14 days. A saline solution was administered to control animals. Behavior tests were performed after 3 and 14 days of treatment. Our findings revealed that LYT treatment improved the neurological outcome, decreased cerebral infarction volume, and reduced apoptosis. Additionally, LYT improved neural plasticity, as the expression of synaptophysin, microtubule associated protein, and myelin basic protein was upregulated by LYT treatment, while neurofilament 200 expression was reduced. Moreover, levels of brain derived neurotrophic factor and basic fibroblast growth factor were increased. Our results suggest that LYT treatment may protect against ischemic injury and improve neural plasticity.

Improvement of hematoma absorption and neurological function in patients with acute intracerebral hemorrhage treated with Xueshuantong.

Spontaneous intracerebral hemorrhage (ICH) leads to high mortality and morbidity. Currently, there is no effective therapy for ICH. Herein we conducted a clinical study in patients with acute ICH to investigate the efficacy of Xueshuantong Injection, a Chinese herbal prescription known for treatment of ischemic diseases in China. Patients (n=63) were randomly assigned to control (n=29) and Xueshuantong Injection treatment (175 mg/d, n=34) groups. Both groups were evaluated using their history and vital signs. The National Institutes of Health Stroke Scale (NIHSS) scores, hematoma volume by CT scanning, and inflammatory factors were assessed before and after two weeks treatment. There were no significant differences in all parameters between two groups before treatment. The treatment group showed significant decreases in both NIHSS score and hematoma volume, compared to control group after treatment (P<0.01 and P<0.05, respectively). Furthermore, the inflammatory factors, as measured by leukocytes, neutrophil percentage and C-reactive protein values, were significantly reduced in treatment group compared to control group after treatment (P<0.05, P<0.05, P<0.01 respectively). Our results showed that treatment with Xueshuantong Injection reduced inflammatory response and increased hematoma absorption, which significantly improved recovery of neurological function. This suggests Xueshuantong Injection as a potential treatment of patients with acute ICH.