Arsenic induced dissolution of neural architecture and signaling are restored through MMPs and AChE inactivation by tea flavonoids in rat, in-silico and in-vitro purified enzyme/theaflavin reaction.

Abstract Chronic arsenic-exposure causes gastro-intestinal/nephrotoxic/neurodegenerative disorders with keratosis/melanosis and cancers. The reactive-oxygen-species (ROS) cause intrinsic-antioxidant (thiols/uric-acid) depletion eventuating cytoskeletal-extracellular-matrix and DNA damage. Therapeutic chelating-agents have multiple side-effects. The protective potential of tea-extract against arsenic neurotoxicity was studied. Influence of uric-acid in arsenic-toxicity was verified. Camellia sinensis (CS dry-leaves) 10mg/ml aqueous), uric-acid (UA) or allopurinol (Allo- urate-depletor) was supplemented to arsenic-intoxicated (0.6 ppm/100g bw/day/4-weeks) female albino-rats and cytotoxicity/biochemistry/histo-architecture/matrix-integrity and DNA-stability were evaluated in their cerebrum-cerebellum. In-vitro purified theaflavin-derivatives were tested on purified-AchE (acetyl-cholinesterase). Higher malondialdehyde, lactate-dehydrogenase and lower uric-acid levels were observed in the arsenic/Allo groups. Degenerations of cerebrum/cerebellum by higher matrix-metalloprotease (MMP2/9)/DNA-damages (comets) are observed. The CS-group restored the adverse-markers, protected tissues/DNA integrity which is supported in the UA-group and opposed in the Allo-group. Impairment of the neural-signaling, evident from the arsenic-exposed animal with unstable-movement/vertigo/tremor accompanied with higher AchE in the cerebellum is significantly restored/protected in the CS-group. This suggests that the neural integrity is maintained by the cellular intrinsic antioxidative-capacity, shown in catalase-SOD1 activities. In-vitro and in silico studies suggest that the theaflavin derivatives (pure, SIGMA) i.e theaflavin-digallate (TFDG) showed the strongest inhibition on purified (SIGMA) AchE (IC50 = 2.19 µg/ml) followed by TFMG (IC50 = 3.86 µg/ml). The4 CS is protective in arsenic-toxicity. Theaflavin-gallate is a strong AchE inhibitor which can be used in arsenic-induced neuro-muscular depletion. Beside antioxidant/anti-inflammatory/anti-carcinogenic role CS restores intrinsic-antioxidants.