Cansheng Zhu

Simvastatin Prevents Dopaminergic Neurodegeneration in Experimental Parkinsonian Models: The Association with Anti-Inflammatory Responses

Background In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinsons disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors. Methodology/Principal Findings Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [3H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha). Conclusions/Significance Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.

Simvastatin Induces Neuroprotection in 6-OHDA-Lesioned PC12 via the PI3K/AKT/Caspase 3 Pathway and Anti-Inflammatory Responses

In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI3K/AKT/caspase 3 pathway are strongly implicated in dopaminergic neuronal death in Parkinsons disease (PD). This study aims to investigate how simvastatin affects 6‐hydroxydopamine‐lesioned PC12 via regulating PI3K/AKT/caspase 3 and modulating inflammatory mediators.

Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-κB pathway in microglia cells.

Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-κB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS-stimulated microglia were blocked after IκB-α was silenced with IκB-α siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases.

Low antioxidant status of serum uric acid, bilirubin and albumin in patients with neuromyelitis optica.

Background:  Oxidative stress plays a central role in neuropathology of multiple sclerosis (MS). The patients with MS have low antioxidant status. Antioxidant therapy may represent an attractive treatment of MS. However, the relationship between neuromyelitis optica (NMO), a distinct nosologic entity or a form of MS, and antioxidant status has not fully been investigated.

The Combination of Homocysteine and C-Reactive Protein Predicts the Outcomes of Chinese Patients with Parkinson's Disease and Vascular Parkinsonism

Background The elevation of plasma homocysteine (Hcy) and C-reactive protein (CRP) has been correlated to an increased risk of Parkinsons disease (PD) or vascular diseases. The association and clinical relevance of a combined assessment of Hcy and CRP levels in patients with PD and vascular parkinsonism (VP) are unknown. Methodology/Principal Findings We performed a cross-sectional study of 88 Chinese patients with PD and VP using a clinical interview and the measurement of plasma Hcy and CRP to determine if Hcy and CRP levels in patients may predict the outcomes of the motor status, non-motor symptoms (NMS), disease severity, and cognitive declines. Each patients NMS, cognitive deficit, disease severity, and motor status were assessed by the Nonmotor Symptoms Scale (NMSS), Mini-Mental State Examination (MMSE), the modified Hoehn and Yahr staging scale (H&Y), and the unified Parkinsons disease rating scale part III (UPDRS III), respectively. We found that 100% of patients with PD and VP presented with NMS. The UPDRS III significantly correlated with CRP (P = 0.011) and NMSS (P = 0.042) in PD patients. The H&Y was also correlated with Hcy (P = 0.002), CRP (P = 0.000), and NMSS (P = 0.023) in PD patients. In VP patients, the UPDRS III and H&Y were not significantly associated with NMSS, Hcy, CRP, or MMSE. Strong correlations were observed between Hcy and NMSS as well as between CRP and NMSS in PD and VP. Conclusions/Significance Our findings support the hypothesis that Hcy and CRP play important roles in the pathogenesis of PD. The combination of Hcy and CRP may be used to assess the progression of PD and VP. Whether or not anti-inflammatory medication could be used in the management of PD and VP will produce an interesting topic for further research.

The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice.

Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evans blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezils neuroprotective activities in MS.

The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis

Abstract Objective: This study aims to assess the protective effect of berberine against neuronal damage in the brain parenchyma of mice with experimental autoimmune encephalomyelitis (EAE). Methods: EAE was induced in female C57 BL/6 mice with myelin oligodendrocyte glycoprotein 35–55 amino acid peptide. The berberine treatment was initiated on the day of disease onset and administered daily until the mice were sacrificed. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, gelatin gel, and gelatin in situ zymography were analysed in this study. Results: Berberine reduced the TUNEL-positive neuronal cells of EAE mice. Gelatin gel and gelatin in situ zymography showed up-regulation of gelatinase activity, which was mainly located in neurons and colocalized with remarkable laminin degradation in EAE mice. Berberine significantly inhibited gelatinase activity and reduced the laminin degradation in EAE mice. Discussion: Our data suggest that berberine could provide protection against neuronal damage in EAE by inhibiting gelatinase activity and reducing laminin degradation. These findings provide further support that berberine can be a potential therapeutic agent for multiple sclerosis.

Association of serum gamma-glutamyltransferase with arterial stiffness in established coronary artery disease.

Serum gamma-glutamyltransferase (GGT) has been reported to predict vascular risk. We enrolled 978 patients (507 men and 471 women) with established coronary artery disease (CAD). The GGT, brachial–ankle pulse wave velocity ([baPWV] to assess arterial stiffness), and conventional risk factors were evaluated. The means of baPWV tend to increase in both genders according to GGT tertiles. Body mass index, GGT, logarithmical (systolic blood pressure [LnSBP]), uric acid (UA), total bilirubin, Ln (cholinesterase), and Ln (total cholesterol) were correlated with baPWV in men in a multivariate model. However, only GGT, LnSBP, UA, and Ln (high-density lipoprotein cholesterol) were correlated with baPWV in women. The GGT was a significant determinant for increased baPWV both in men (β = 0.017; P < .001) and in women (β = 0.015; P < .001). In conclusion, GGT was independently associated with increased arterial stiffness both in men and in women with established CAD.

Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice.

Previous studies have suggested that minocycline can attenuate cognitive deficits in animal models of conditions such as Alzheimers disease and cerebral ischemia through inhibiting microglia associated anti-inflammatory actions. However the pathway that minocycline targets to enhance cognitive performance is not fully defined. Here we examined the effects of minocycline on learning and memory in aged (22-month-old) C57 BL/6 mice. We treated one group of mice with minocycline (30 mg/kg/day), and another group of mice with donepezil (2 mg/kg/day) as a positive control. The Morris water maze and passive avoidance tests were used to evaluate the effects of minocycline on learning and memory deficits. We also used high-frequency stimulation-induced long-term potentiation and Golgi-Cox staining to assess the effect of minocycline on synaptic plasticity and synaptogenesis. The effects of minocycline on synapse-associated signaling proteins were determined by western blot. We found that minocycline ameliorates cognitive deficits, enhances neuroplasticity, activates brain-derived neurotrophic factor- extracellular signal-regulated kinases signaling and increases expression of Arc, EGR1 and PSD-95 in the CA1 and dentate gyrus regions of the hippocampus in aged mice. The effects of minocycline in aged mice were similar to those of donepezil. Our results suggest that minocycline could improve learning and memory through enhancing synaptic plasticity and synaptogenesis, modulating the expression of synapse-associated signaling proteins, which provide a rationale for exploring the viability of using minocycline treatment in cognitive deficits.

Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis

Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities. However, few studies have been carried out to assess its effects on the expression of neurotrophins in experimental autoimmune encephalomyelitis or multiple sclerosis. Here we investigated the alteration of brain-derived neurotrophic factor and nerve growth factor in the sera, cerebral cortex, and lumbar spinal cord of experimental autoimmune encephalomyelitis C57 BL/6 mice in vivo as well as the splenocytes culture supernatants in vitro after minocycline administration. Our results demonstrated that minocycline could up-regulate the expression of brain-derived neurotrophic factor and nerve growth factor both in peripheral (sera and splenocytes culture supernatants) and target organs (cerebral cortex and lumber spinal cord) of mice with experimental autoimmune encephalomyelitis. These data suggest that up-regulation of neurotrophins in experimental autoimmune encephalomyelitis may be a novel neuroprotective mechanism of minocycline.