Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. The present study evaluates the ability of peptide corresponding to the NF-κB essential modifier-binding domain (NBD) of IκB kinase α (IKKα) or IKKβ to prevent nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and establish a role for NF-κB in human parkinsonism. First, we found that NF-κB was activated within the substantia nigra pars compacta of PD patients and MPTP-intoxicated mice. However, i.p. injection of wild-type NBD peptide reduced nigral activation of NF-κB, suppressed nigral microglial activation, protected both the nigrostriatal axis and neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These findings were specific because mutated NBD peptide had no effect. We conclude that selective inhibition of NF-κB activation by NBD peptide may be of therapeutic benefit for PD patients.     

Altered Spinal MicroRNA‐146a and the MicroRNA‐183 Cluster Contribute to Osteoarthritic Pain in Knee Joints

The objective of this study was to examine whether altered expression of microRNAs in central nervous system components is pathologically linked to chronic knee joint pain in osteoarthritis. A surgical animal model for knee joint OA was generated by medial meniscus transection in rats followed by behavioral pain tests. Relationships between pathological changes in knee joint and development of chronic joint pain were examined by histology and imaging analyses. Alterations in microRNAs associated with OA‐evoked pain sensation were determined in bilateral lumbar dorsal root ganglia (DRG) and the spinal dorsal horn by microRNA array followed by individual microRNA analyses. Gain‐ and loss‐of‐function studies of selected microRNAs (miR‐146a and miR‐183 cluster) were conducted to identify target pain mediators regulated by these selective microRNAs in glial cells. The ipsilateral hind leg displayed significantly increased hyperalgesia after 4 weeks of surgery, and sensitivity was sustained for the remainder of the 8‐week experimental period (F = 341, p < 0.001). The development of OA‐induced chronic pain was correlated with pathological changes in the knee joints as assessed by histological and imaging analyses. MicroRNA analyses showed that miR‐146a and the miR‐183 cluster were markedly reduced in the sensory neurons in DRG (L4/L5) and spinal cord from animals experiencing knee joint OA pain. The downregulation of miR‐146a and/or the miR‐183 cluster in the central compartments (DRG and spinal cord) are closely associated with the upregulation of inflammatory pain mediators. The corroboration between decreases in these signature microRNAs and their specific target pain mediators were further confirmed by gain‐ and loss‐of‐function analyses in glia, the major cellular component of the central nervous system (CNS). MicroRNA therapy using miR‐146a and the miR‐183 cluster could be powerful therapeutic intervention for OA in alleviating joint pain and concomitantly regenerating peripheral knee joint cartilage. © 2013 American Society for Bone and Mineral Research.     

Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine

Tumor necrosis factor-alpha (TNF-α) is widely known to be involved in physiological and pathophysiological processes of the brain where this proinflammatory cytokine is implicated with regulation of inflammatory and survival components. We report that TNF-α up-regulates exon-IV-bdnf mRNA and brain-derived neurotrophic factor (BDNF) protein in primary astrocytes. The BDNF protein was detectable both in cellular lysate and in the extracellular medium. Activation of NF-κB by TNF-α and inhibition of TNF-α-induced BDNF expression by Δp65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-κB) suggests that TNF-α induces BDNF expression through the activation of NF-κB. Similarly, TNF-α induced the activation of C/EBPβ and the expression of BDNF was sensitive to overexpression of ΔC/EBPβ (a dominant-negative mutant) and ETO (an inhibitor of C/EBPβ). Among three MAP kinases, TNF-α-induced BDNF up-regulation was sensitive only to inhibitors of ERK MAP kinase. However, the ERK MAP kinase pathway was coupled to activation of C/EBPβ but not NF-κB. Taken together, this study identifies a novel property of TNF-α in inducing the expression of BDNF via NF-κB and C/EBPβ in astrocytes that may be responsible for neurotrophic activity of the cytokine.     

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Neuroprotective Parkinson Disease Protein DJ-1 in Astrocytes and Neurons

DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21^ras farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21^ras alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21^ras in DJ-1 expression. However, an inhibitor of geranyl geranyl transferase (GGTI) and a dominant-negative mutant of p21^rac had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21^ras, but not p21^rac, is involved in the regulation of DJ-1.     

Sphingolipids in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the CNS. Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), are target cells in MS. Although the etiology of MS is poorly known, new insights suggest oligodendrocyte apoptosis as one of the critical events followed by glial activation and infiltration of lymphocytes and macrophages. A major breakthrough in delineation of the mechanism of cell death, perivascular cuffing, and glial activation came from elucidation of the sphingolipid signal transduction pathway. The sphingolipid signal transduction pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and downstream targets. Sphingomyelin, a major component of myelin membrane formed by mature oligodendrocytes, is abundant in the CNS and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Similarly, under certain conditions, sphingosine produced from ceramide by ceramidase is phosphorylated by sphingosine kinases to sphingosine-1 phosphate, another potent second messenger molecule. Both ceramide and sphingosine-1 phosphate regulate life and death of many cell types including brain cells and participate in pathogenic processes of MS. In this review, we have made an honest attempt to compile recent findings made by others and us relating to the role of sphingolipids in the disease process of MS.     

PPARα serves as a new receptor of aspirin for neuroprotection

Acetyl salicylic acid, commonly known as aspirin, has been being widely used as an anti-inflammatory drug for almost 100 years. However, there was no receptor known for this popular drug. Recently, we have established that peroxisome proliferator-activated receptor alpha (PPARα) acts as a novel receptor of aspirin. Activation of PPARα by aspirin stimulated a series of downstream signaling pathways that could potentially ameliorate different Alzheimer's disease (AD)-related pathologies. In this mini-review, we have discussed how aspirin–PPARα interaction plays a pivotal role in the amelioration of AD pathology via the stimulation of neurotrophic factors, upregulation of plasticity-associated genes, and removal of plaque burden in hippocampal neurons.     

A Broad Application of CRISPR Cas9 in Infectious,Inflammatory and Neurodegenerative Diseases

Journal of Neuroimmune Pharmacology - Being the most important immune-responsive cell type of the CNS, microglia always glorify the so-called crossroad of Neurology, Immunology and Pharmacology. As...