[Show abstract][Hide abstract] ABSTRACT: 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 Evan's 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 donepezil's neuroprotective activities in MS.
[Show abstract][Hide abstract] ABSTRACT: This study aims to assess the protective effect of berberine against neuronal damage in the brain parenchyma of mice with experimental autoimmune encephalomyelitis (EAE).
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.
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.
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.
Neurological Research 05/2013; 35(4):360-8. DOI:10.1179/1743132812Y.0000000156 · 1.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
European journal of pharmacology 05/2012; 686(1-3):124-9. DOI:10.1016/j.ejphar.2012.04.043 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS). Although there are several approved drugs for MS, not all patients respond optimally to these drugs. More effective, well-tolerated therapeutic strategies for MS are necessary, either through the development of new medication or combination of existing ones. Minocycline is a traditional antibiotic with profound anti-inflammatory and neuroprotective effects and good tolerance for long-term use. The encouraging results from the animal model and clinical experiments on minocycline make it a promising candidate for MS treatment whether used alone or combined with other drugs. In this review, we summarized the pharmacological actions of minocycline and focused on its therapeutic effects and safety in experimental autoimmune encephalomyelitis (EAE) and MS. The data obtained here showed that minocycline would be an effective and safe therapy for MS.
Journal of neuroimmunology 06/2011; 235(1-2):1-8. DOI:10.1016/j.jneuroim.2011.04.006 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Berberine, an isoquinoline derivative alkaloid, has a wide range of pharmacological properties and is considered to have anti-inflammatory and neuroprotective effects. However, there are no reports about the effects and mechanisms of berberine in experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS).
Female C57 BL/6 mice immunized with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide were treated with berberine at the day of disease onset and medication was administered daily until mice were sacrificed. Blood-brain barrier (BBB) permeability and the alteration of matrix metalloproteinase-2 (MMP-2, 72 kDa) and matrix metalloproteinase-9 (MMP-9, 92 kDa) in the brain and cerebrospinal fluid (CSF) of EAE mice were detected by quantitative measurement for Evan's blue (EB) content, Western blot and gelatin zymography respectively. The results showed that berberine attenuated clinical and pathological parameters of EAE, reduced the permeability of BBB, inhibited the activity and expression of MMP-9 but not MMP-2 in the CSF and brain of EAE mice.
These findings suggest that berberine is effective to attenuate the clinical severity of EAE in C57 BL/6 mice by reducing the permeability of BBB, decreasing the expression and activity of MMP-9, and decreasing the inflammatory infiltration. We think that berberine might be a potential therapeutic agent for MS.
PLoS ONE 10/2010; 5(10):e13489. DOI:10.1371/journal.pone.0013489 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Combination therapies with existing or novel drugs for multiple sclerosis (MS) have great clinical potential to improve MS treatment outcomes. Our previous studies had confirmed that the combined treatment of minocycline and prednisone produced beneficial effects partially through preventing the reduction of brain-derived neurotrophic factor and nerve growth factor mRNA expression in the cerebral cortex of experimental autoimmune encephalomyelitis (EAE) mice. As high-dose methylprednisolone administered intravenously has more superior efficacy than oral prednisone and had been provided as a stable therapy for MS patients at the onset of an acute relapse, we further evaluated the effects of combined methylprednisolone and minocycline at suboptimal doses on EAE mice at the acute stage in this study. Interferon gamma (IFN-γ) and interleukin-4 (IL-4), the hallmark cytokines that direct Th1 and Th2 development and play an important role in the pathogenesis of MS as well as EAE, were also assayed. Obtained results showed that combined treatment could successfully attenuate severe clinical deficit and suppress histopathological events in EAE. In addition, reduced IFN-γ and increased IL-4 production/expression were found in the splenocytes culture supernatants and brains of EAE mice by the combined treatment. Our data indicate that the combination of methylprednisolone and minocycline may be a promising therapy for MS.
Journal of neuroimmunology 09/2010; 226(1-2):104-9. DOI:10.1016/j.jneuroim.2010.05.039 · 2.47 Impact Factor