Rishi Pal

Role of neuroinflammation and latent transcription factors in pathogenesis of Parkinson’s disease

Parkinson’s disease (PD) the second most common age-associated progressive neurodegenerative disorder is characterized by loss of dopaminergic neurons, cytoplasmic inclusions of aggregated proteins (Lewy bodies), and neuroinflammation. The inflammation of neurons causes release of various inflammatory mediators (IFNs, EGF, IL5, IL6, HGF, LIF and BMP2). The hallmarks of neuroinflammation are the presence of activated microglia and reactive astrocytes in the parenchyma of the CNS and increased production of cytokines, chemokines, prostaglandins, complement cascade proteins, and reactive oxygen and nitrogen species (ROS/RNS) which in some cases can result in disruption of the blood brain barrier and direct participation of the adaptive immune system. Latent transcription factors such as NF-κB, STAT 3, AP1, and SMAD 7, Toll like receptors and FAF 1 are constitutively upregulated in activated microglia. Toll-like receptors when activated promote NF-κB signaling thus promoting a vicious cycle of neuroinflammation. These transcription factors take dopaminergic neurons to apoptotic pathway via p53 and other death domain receptors. Neuroprotective signaling pathways such as mTOR, SOCS, and TGF-β down regulated during development of PD. YY1 signaling, which has protective effect against α-Synuclein toxicity, is significantly decreased in PD patients. In summary we can say that transcription factors promoting inflammation such as NF-κB, STAT 3, AP 1, and Toll-like receptors are constitutively upregulated in PD, while neuroprotective pathways such as mTOR, TGF-β, and YY1 are substantially downregulated in microglia of PD patients.

Protective role of theophylline and their interaction with nitric oxide (NO) in adjuvant-induced rheumatoid arthritis in rats.

Theophylline (non-specific PDE inhibitor) and their interactions with nitric oxide modulators were evaluated in adjuvant-induced arthritic model of rats. Wistar rats (200-300g), 8 animals per group were used in the study. The animals were injected with 0.1mL of squalene and 0.2mL of complete Freunds adjuvant on day (0) in sub-planter region of right hind paw controls received only saline. The treatment with theophylline and nitric oxide modulators were done from day 14 to day 28. Arthritis indexes, ankle diameter, paw volume, and body weight were determined to assess RA progression from day (0) to day 28. On day 28 animals were sacrificed and their blood collected for IL-10 and TNF-α cytokine levels and hind paw for pathological analysis. Synovial fluid from joint spaces of CFA inoculated rats was collected to estimate TNF-α level in synovial fluid. The data obtained was analyzed by two-way ANOVA followed by the Newman-Keuls post-hoc test. Theophylline (10 and 20mg/kg) significantly decreased adjuvant induced increased arthritis-index, paw volume and ankle diameter (p<0.05 in all parameters) compared to only adjuvant control group. It also reversed adjuvant induced slight decrease in body weight to normalcy. l-Arginine 100mg/kg+theophylline 20mg/kg suppressed TNF-α and elevates IL-10 level as well as reversed adjuvant-induced elevated arthritic parameters as compared to only adjuvant and prednisone group (p<0.001). Synovial TNF-α level of adjuvant only group was several fold higher than its serum level. Treatment with theophylline 20mg/kg significantly reduces synovial TNF-α level as compared to adjuvant only group. Theophylline 20mg/kg+L-NAME 10mg/kg significantly reversed these adjuvant-induced changes in immunological, histopathological and arthritis parameters (p<0.05).

Food-Based Therapeutics: A Converging Paradigm of Traditional and Modern Food Science

Ayurveda, the art of medical treatment native to India, is a form of traditional medicine that is now regarded as a complementary and alternative medicine (CAM) by the developed world. It utilizes the potential of natural substances, for example, plants, herbs, fruits, and heavy metals, in the treatment of disease conditions. Food is also derived from these natural resources due to which, besides its nutritional value, also possesses medicinal value for human beings. Medical science, including modern medicine, recognizes the importance of food products in the prevention and, to some extent, treatment of many diseases. Ayurveda utilizes crude plant products for therapeutic purposes, while modern medicine uses purified extracts of the same products as drugs. With advances in food science, it is being realized that food may also be used in the prevention of many diseases such as, for example, Alzheimer’s disease, diabetes mellitus, obesity, and cancer. The ancient science of Ayurveda gets its inspiration for treatment with these natural resources from Charaka Samhita, while modern food science/medicine tends to find scientific evidence for their use as therapeutics. With advancements in scientific techniques that can utilize Ayurvedic scientific knowledge and clinical experience for the scientific validation of traditional Indian and Chinese food-based therapeutics, the use of reverse pharmacology is in progress. Thus, there is a need to explore food-based drug discovery based on Indian and Chinese traditional medicine from clinic to laboratory using a reverse pharmacology approach. Here we describe such food-based therapeutics with selected examples based on previous studies.