withaferin-a and Encephalitis

Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute a therapeutic target for TDP-43-mediated disease. Here, we investigated the effects of root extract of Withania somnifera (Ashwagandha), an herbal medicine with anti-inflammatory properties, in transgenic mice expressing a genomic fragment encoding human TDP-43

Topics: Amyotrophic Lateral Sclerosis; Animals; Avoidance Learning; Cells, Cultured; Cytokines; Disease Models, Animal; DNA-Binding Proteins; Encephalitis; Female; Frontotemporal Lobar Degeneration; Male; Mice; Mice, Transgenic; Microglia; Motor Activity; Neuromuscular Junction; Neurons; NF-kappa B; Plant Extracts; Rotarod Performance Test; Spinal Cord; TDP-43 Proteinopathies; Withania

Several lines of evidence suggest that astrocytes play a key role in modulating the immune responses of the central nervous system (CNS) to infections, injuries, or pathologies. Yet, their contribution to these processes remains mostly elusive. Astroglia are endowed with a wide range of toll-like receptors (TLR) by which they can sense infectious agents as well as endogenous danger signals released by damaged cells. Here we demonstrate that the activation of astrocytic TLR4 by bacterial lipopolysaccharide (LPS) challenge can promote nuclear factor κB (NF-κB)-dependent induction of pro-inflammatory and stress response mediators, particularly Tumor Necrosis Factor α (TNFα), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). Since the steroid lactone Withaferin A was described to inhibit NF-κB activity in different cell types, we next determined the impact of this natural compound towards the identified astrocytic signalling pathway. Innate immune activation was induced by stimulation of the LPS/TLR4 axis in spinal cord astrocytes. We provide evidence that both pre-treating and post-treating the cells with Withaferin A attenuate astrocytic NF-κB activity as well as the consequent production of TNFα, COX-2, and iNOS induced by stimulation of the LPS/TLR4 pathway. This study suggests that Withaferin A may be an eligible candidate for the treatment of neuroinflammatory and stress conditions characterized by an important astrocytic input.

Topics: Antineoplastic Agents, Phytogenic; Astrocytes; Cell Line, Tumor; Cyclooxygenase 2; Encephalitis; Humans; Lipopolysaccharides; NF-kappa B p50 Subunit; Nitric Oxide Synthase Type II; Signal Transduction; Spinal Cord; Stress, Psychological; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Withanolides