Zhen-Zhen Wang

Selective modulation of microglia polarization to M2 phenotype for stroke treatment

Resident microglia are the major immune cells in the brain, acting as the first defense of the central nervous system. Following cerebral ischemia, microglia respond to this injury at first and transform from surveying microglia to active state. The activated microglia play a dual role in the ischemic injury, due to distinct microglia phenotypes, including deleterious M1 and neuroprotective M2. However, microglia show transient M2 phenotype followed by a shift to M1. The high ratio of M1 to M2 is significantly related to ischemic injury. Many signal pathways participate in the alternation of microglial phenotype, presenting potential therapeutic targets for selectively modulating M2 polarization of microglia. In this review, we discuss how the M2 phenotype mediates neuroprotective effects and summarize the alternation of signaling cascades that control microglial phenotype after ischemic stroke.

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Aim:Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntingtons disease (HD) and explored the mechanisms of action.Methods:Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2–5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting.Results:3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC.Conclusion:Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.

Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid.

Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors.

Systematic review of traditional chinese medicine for depression in Parkinson's disease.

Depression is the most common non-motor symptom of Parkinsons disease (PD). Recent clinical trials have evaluated the effectiveness of traditional Chinese medicine (TCM) in the treatment of depression in PD (dPD). However, the results are conflicting rather than conclusive. To investigate the effectiveness of TCM for the treatment of dPD, a systematic review was conducted. Literature searches and collections were performed to identify studies addressing the treatment of TCM for dPD. The methodological quality and risk of bias in all studies included were evaluated. Weighted mean difference (WMD) with 95% confidence interval (CI) was used as the effect measure. Finally, a total of 10 studies involving 582 patients were identified. The pooled results revealed that TCM combined with conventional drugs significantly improved the total scores of the unified Parkinsons disease rating scale (WMD = -7.35, 95% CI: -11.24 to -3.47) and the score of the Hamilton rating scale for depression (HAM-D) (WMD = -4.19, 95% CI: -5.14 to -3.24) compared with conventional drug, respectively. Conclusively, there is evidence that TCM may be beneficial to the treatment of dPD in spite of the methodological weakness of the included studies.

DJ-1 regulating PI3K-Nrf2 signaling plays a significant role in bibenzyl compound 20C-mediated neuroprotection against rotenone-induced oxidative insult

Oxidative stress is thought to be involved in the development of Parkinsons disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β (GSK3β) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future.

Developmental expression of chemokine-like factor 1, a novel member of chemokines family, in postnatal rat cerebral cortex.

Chemokine-like factor 1 (CKLF1) has been implicated to induce the migration of neuroblastoma cells and is abundant in fetal brain but scarce in adult brain. Given the importance of neural cell migration in brain development, it is possible that the chemotaxis of CKLF1 is required during brain development. Therefore, it is essential to know the detailed expression profiles of CKLF1 during brain development first. However, the developmental expression patterns of CKLF1 still remain unclear. We aimed to investigate the temporal and spatial expressions of CKLF1 during cerebral cortex postnatal development in rats. By reverse-transcription PCR/immunoblotting at multiple time points, the mRNA/protein expressions of CKLF1 were in abundance at birth, then decreased progressively within the next two weeks and almost disappeared in adulthood. By immunohistochemistry staining, an obvious expression of CKLF1 was observed in the cerebral cortex, hippocampus, olfactory bulb, some specific nuclei and commissural fibers. Concluding, the temporal expression pattern of CKLF1 was coincident with the postnatal developmental stages and the spatial locations of CKLF1 were some destinations of neural cell migration or regions where myelination normally occurs during cerebrum postnatal development.

Overexpression of DJ‐1/PARK7, the Parkinson's disease‐related protein, improves mitochondrial function via Akt phosphorylation on threonine 308 in dopaminergic neuron‐like cells

DJ‐1/PARK7, the Parkinsons disease‐related protein, plays an important role in mitochondrial function. However, the mechanisms by which DJ‐1 affects mitochondrial function are not fully understood. Akt is a promoter of neuron survival and is partly involved in the neurodegenerative process. This research aimed at investigating a possible relationship between DJ‐1 and Akt signalling in regulating mitochondrial function in the dopaminergic neuron‐like cells SH‐SY5Y and PC‐12. Overexpression of DJ‐1 was firstly validated at both the transcriptional and translational levels after transit transfection with plasmid pcDNA3‐Flag‐DJ‐1. Confocal fluorescence microscopy demonstrated that overexpression of DJ‐1 increased the mitochondrial mass, but did not disrupt the mitochondrial morphology. In addition, mitochondrial complex I activity was raised in DJ‐1‐overexpressing cells, and this rise occurred with an increase in cellular adenosine 5′‐triphosphate content. Moreover, immunoblotting demonstrated that the levels of phosphoinositide 3‐kinase and the total Akt were not altered in DJ‐1‐overexpressing cells, and nor was the Akt phosphorylation on serine 473 changed. By contrast, Akt phosphorylation on threonine 308 was significantly augmented by overexpression of DJ‐1, and the expression of glycogen synthase kinase‐3beta, a downstream effector of Akt, was suppressed. In summary, these results suggest that overexpression of DJ‐1 improves the mitochondrial function, at least in part, through a mechanism involving Akt phosphorylation on threonine 308.

Lack of association between p.Ser167Asn variant of Parkin and Parkinson's disease: A meta-analysis of 15 studies involving 2,280 cases and 2,459 controls†

Previous clinical trials have evaluated the association between Parkin p.Ser167Asn (c.601G>A) variant and Parkinsons disease (PD) risk. However, the results remain conflicting rather than conclusive. Therefore, we performed this meta‐analysis to assess whether pooled results show the association. We performed structured literature searches for studies addressing the association between the Parkin p.Ser167Asn variant and PD risk. We conducted analyses of study characteristics, heterogeneity, and funnel plot asymmetry in analyses analogous to additive, dominant, recessive, and general genetic models with the odds ratio (OR) as the measure of association. When 15 eligible studies (n = 4,739 subjects) were pooled into the meta‐analysis, there was no evidence for significant association in additive genetic model between Parkin p. Ser167Asn variant and PD risk (OR = 1.02, 95% confidence interval (CI) = 0.83–1.25; P = 0.866). The OR for the dominant model was 1.06 (95% CI = 0.80–1.41) while the OR for the recessive model was 0.90 (95% CI = 0.71–1.14). The OR for the heterozygous was 1.07 (95% CI = 0.80–1.43) while the OR for the homozygotes was 1.19 (95% CI = 0.81–1.74). In the subgroup analysis by ethnicity, no significant association was found in any genetic model. Beggs funnel plot and Eggers test provided visual and statistical evidences for funnel plot symmetry, suggesting no presence of publication bias. In summary, the meta‐analysis strongly suggests that Parkin p. Ser167Asn variant is not associated with PD risk.

Protective effects of DJ-1 medicated Akt phosphorylation on mitochondrial function are promoted by Da-Bu-Yin-Wan in 1-methyl-4-phenylpyridinium-treated human neuroblastoma SH-SY5Y cells.

ETHNOPHARMACOLOGICAL RELEVANCE Da-Bu-Yin-Wan (DBYW), a historically traditional Chinese medicine formula, was originally defined over 600 years ago. In recent decades, DBYW was clinically employed to treat Parkinsons disease (PD). AIM OF THE STUDY To explore the underlying mechanism of DBYW on mitochondrial function, we investigated the effect of DBYW on mitochondrial function from the perspectives of DJ-1 and Akt signaling. MATERIALS AND METHODS Human derived neuroblastoma SH-SY5Y cells were transiently transfected with the plasmid pcDNA3-Flag-DJ-1 aimed to overexpress the DJ-1 protein. Transfected cells were treated with 1-methyl-4-phenylpyridinium (MPP(+)), a PD-related mitochondrial complex I inhibitor, in the absence and presence of DBYW. The cell viability was assessed by Cell Counting Kit-8 assay. The protein expressions of DJ-1 and Akt signaling were examined by western blotting. The mitochondrial mass was evaluated by confocal fluorescence microscopy. The mitochondrial complex I activity and cellular ATP content were measured by commercial kits. RESULTS Transfection with pcDNA3-Flag-DJ-1 decreased the MPP(+)-induced toxicity and overexpressed the DJ-1. In DJ-1 overexpressed cells, the mitochondrial mass was raised, mitochondrial complex I activity was improved, and cellular ATP content was increased. In addition, overexpression of DJ-1 augmented the Akt phosphorylation on threonine 308 and serine 473. Moreover, DBYW promoted the above effects in DJ-1 expressed cells. CONCLUSIONS These data suggest that DJ-1 protects the mitochondrial function by medicating Akt phosphorylation in MPP(+)-treated SH-SY5Y cells. Moreover, DBYW enhances the protective effect of DJ-1 medicated Akt phosphorylation on mitochondrial function.

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice.

Aim:Recent studies show that the extract of a Chinese herb Polygalae Radix exerts cognition-enhancing actions in rats and humans. The aim of this study was to characterize the pharmacological profiles of active compounds extracted from Polygalae Radix.Methods:Two fractions P3 and P6 and two compounds PTM-15 and polygalasaponin XXXII (PGS32) were prepared. Neuroprotective effects were evaluated in primary cortical neurons exposed to high concentration glutamate, serum deficiency or H2O2. Anti-dementia actions were assessed in scopolamine-induced amnesia in mice using step-through avoidance tests and channel water maze tests. After conducting the channel water maze tests, TrkB phosphorylation in mouse hippocampus was detected using Western blotting. Long-term potentiation (LTP) was induced in the dentate gyrus in adult rats; PGS32 (5 μL 400 μmol/L) was injected into the lateral cerebral ventricle 20 min after high frequency stimulation (HFS).Results:Compared to the fraction P6, the fraction P3 showed more prominent neuroprotective effects in vitro and cognition-enhancing effects in scopolamine-induced amnesia in mice. One active compound PGS32 in the fraction P3 exerted potent cognition-enhancing action: oral administration of PGS32 (0.125 mg·kg−1·d−1) for 19 days abolished scopolamine-induced memory impairment in mice. Furthermore, PGS32 (0.5 and 2 mg·kg−1·d−1) significantly stimulated the phosphorylation of TrkB in the hippocampus. Intracerebroventricular injection of PGS32 significantly enhanced HFS-induced LTP in the dentate gyrus of rats.Conclusion:PGS32 attenuates scopolamine-induced cognitive impairments in mice, suggesting that it has a potential for the treatment of cognitive dysfunction and dementia.