Multiple sclerosis (MS) is a chronic human demyelinating disorder of the CNS having an autoimmune connection. At present, about 400,000 people in the United States have MS. It is more common among Caucasians, particularly those of northern European ancestry. Several evidences show a potential link between the incidence of MS and combat service. For example, one study in the Annals of Neurology (2004, 55: 65-71) has identified 5,345 cases of MS among U.S. veterans that were deemed """"""""service-connected."""""""" Although the mechanism is not clear, viral infections, several vaccinations and exposure to different war zone chemicals may increase the risk of having MS. Accordingly, several veterans who served Gulf war 1 as well as many Vietnam veterans have been diagnosed with MS. In spite of extensive research, no effective therapy is available to halt the progression of MS. Inflammation and demyelination are major pathological features of MS and experimental allergic encephalomyelitis (EAE), an animal model of MS. Therefore, suppressing inflammation and promoting remyelination, appear to be crucial therapeutic challenges for MS. While neurotrophins (NGF, NT-3, NT-4/5, and BDNF) and glial cell line-derived neurotrophic factor (GDNF)-related factors (GDNF, neurturin) do not increase myelinogenesis, ciliary neurotrophic factor (CNTF) induces a strong promyelinating effect. Therefore, increasing the level of CNTF in the CNS is an important step in repairing axonal damage in MS. Although gene manipulation and stereotaxic injection of CNTF into the brain are available options, it seems from the therapeutic angle, the best option is to stimulate/induce the production of CNTF within the CNS of patients with MS. Is it really possible? Our preliminary results show that it is possible with aspirin, acetylsalicylic acid, one f the most widely-used analgesics throughout the world. We have discovered that aspirin increases myelinogenic trophic factor CNTF and upregulates anti-inflammatory molecules in astrocytes via involving different peroxisome proliferator-activated receptors (PPARs). Furthermore, oral administration of aspirin reduces clinical symptoms of EAE. This grant is anchored to these exciting findings. From the academic angle, we have dedicated Specific aims I and II to investigate molecular mechanisms behind these novel trophic and anti-inflammatory efficacies of aspirin. From the therapeutic angle, we will test the effect of aspirin on myelinatio and anti-inflammation and the overall disease process of relapsing-remitting, chronic and spontaneous EAE in mice under Specific aim III. A positive outcome will highlight undiscovered properties of aspirin and enhance the possibility of controlling MS by this widely-used drug.

Public Health Relevance

There is a potential link between the incidence of multiple sclerosis (MS) and combat service as several vaccinations (anthrax, hepatitis B), viral infections, CNS toxins, and air pollutants may increase the risk of having MS among veterans. Here, studies proposed from various angles will delineate the efficacy of orally administered low dose of aspirin in upregulating anti-inflammatory molecules and oligodendroglial trophic factor CNTF in the CNS and inhibiting the disease process of EAE, an animal model of MS. A positive outcome will highlight undiscovered properties of aspirin and enhance the possibility of controling MS by this widely-used analgesic.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology C (NURC)
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Jesse Brown VA Medical Center
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Patel, Dhruv; Roy, Avik; Kundu, Madhuchhanda et al. (2018) Aspirin binds to PPAR? to stimulate hippocampal plasticity and protect memory. Proc Natl Acad Sci U S A 115:E7408-E7417
Chandra, Sujyoti; Jana, Malabendu; Pahan, Kalipada (2018) Aspirin Induces Lysosomal Biogenesis and Attenuates Amyloid Plaque Pathology in a Mouse Model of Alzheimer's Disease via PPAR?. J Neurosci 38:6682-6699
Kundu, Madhuchhanda; Roy, Avik; Pahan, Kalipada (2017) Selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12-IFN-?. Proc Natl Acad Sci U S A 114:11482-11487
Kundu, Madhuchhanda; Mondal, Susanta; Roy, Avik et al. (2016) Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Enriches Regulatory T Cells via STAT6-Mediated Upregulation of TGF-?. J Immunol 197:3099-3110
Bera, Swapna; Kar, Rajiv K; Mondal, Susanta et al. (2016) Structural Elucidation of the Cell-Penetrating Penetratin Peptide in Model Membranes at the Atomic Level: Probing Hydrophobic Interactions in the Blood-Brain Barrier. Biochemistry 55:4982-96
Modi, Khushbu K; Jana, Malabendu; Mondal, Susanta et al. (2015) Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Ciliary Neurotrophic Factor in Astrocytes and Oligodendrocytes. Neurochem Res 40:2333-47
Roy, Avik; Jana, Malabendu; Kundu, Madhuchhanda et al. (2015) HMG-CoA Reductase Inhibitors Bind to PPAR? to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. Cell Metab 22:253-65
Jana, Malabendu; Mondal, Susanta; Jana, Arundhati et al. (2014) Interleukin-12 (IL-12), but not IL-23, induces the expression of IL-7 in microglia and macrophages: implications for multiple sclerosis. Immunology 141:549-63
Pahan, Kalipada (2013) Multiple Sclerosis and Experimental Allergic Encephalomyelitis. J Clin Cell Immunol 4:
Roy, Avik; Pahan, Kalipada (2013) Myelin Basic Protein-primed T Helper 2 Cells Suppress Microglial Activation via AlphaVBeta3 Integrin: Implications for Multiple Sclerosis. J Clin Cell Immunol 7:158

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