Pharmacological investigations on efficacy of Phlorizin a sodium-glucose co-transporter (SGLT) inhibitor in mouse model of intracerebroventricular streptozotocin induced dementia of AD type.

OBJECTIVES: The study has been commenced to discover the potential of Phlorizin (dual SGLT inhibitor) in streptozotocin induced dementia of Alzheimer's disease (AD) type. MATERIAL AND METHODS: Injection of Streptozotocin (STZ) was given via i.c.v. route (3 mg/kg) to induce dementia of Alzheimer's type. In these animals learning and memory was evaluated using Morris water maze (MWM) test. Glutathione (GSH) and thiobarbituric acid reactive species (TBARS) level was quantified to evaluate the oxidative stress; cholinergic activity of brain was estimated in term of acetylcholinesterase (AChE) activity; and the levels of myeloperoxidase (MPO) were measured as inflammation marker. RESULTS: The mice model had decreased performance in MWM, representing impairment of cognitive functions. Biochemical evaluation showed rise in TBARS level, MPO and AChE activity, and fall in GSH level. The histopathological study revealed severe infiltration of neutrophils. In the study, Phlorizin/Donepezil (serving as positive control) treatment mitigate streptozotocin induced cognitive decline, histopathological changes and biochemical alterations. CONCLUSIONS: The results suggest that Phlorizin decreased cognitive function via its anticholinesterase, antioxidative, antiinflammatory effects and probably through SGLT inhibitory action. It can be conferred that SGLTs can be an encouraging target for the treatment of dementia of AD.

Functional characterization of intracellular pH regulators responsible for acid extrusion in human radial artery smooth muscle cells.

Intracellular pH (pHi) is a critical factor influencing many important cellular functions. Acid extrusion carriers such as an Na⁺/H⁺ exchanger (NHE) Na⁺/HCO3⁻ cotransporter (NBC) and monocarboxylate transporters (MCT) can be activated when cells are in an acidic condition (pHi < 7.1). Human radial artery smooth muscle cells (HRASMC) is an important conduit in coronary artery bypass graft surgery. However, such far, the pHi regulators have not been characterized in HRASMCs. We therefore investigated the mechanism of pHi recovery from intracellular acidosis and alkalosis, induced by NH4Cl-prepulse and Na-acetate-prepulse, respectively, using intracellular 2',7'-bis(2-carboxethyl)-5(6)- carboxy-fluorescein (BCECF)-fluorescence in HRASMCs. Cultured HRASMCs were derived from the segments of human radial artery that were obtained from patients undergoing bypass grafting. The resting pHi is 7.22 ± 0.03 and 7.17 ± 0.02 for HEPES- (nominally HCO3⁻-free) and CO2/HCO3⁻- buffered solution, respectively. In HEPES-buffered solution, a pHi recovery from induced intracellular acidosis could be blocked completely by 30 µM HOE 694 (3-methylsulfonyl-4-piperidinobenzoyl, guanidine hydrochloride) a specific NHE inhibitor, or by removing [Na⁺]0. In 3% CO2/HCO3⁻-buffered solution, HOE 694 slowed the pHi recovery from the induced intracellular acidosis only, while adding together with DIDS (a specific NBC inhibitor) or removal of [Na⁺]0 entirely inhibited the acid extrusion. Moreover, α-cyano-4-hydroxycinnamate (CHC; a specific blocker of MCT) blocked the lactate-induced pHi changes. In conclusion, we demonstrate, for the first time, that 3 different pHi regulators responsible for acid extruding, i.e. NHE and NBC, and MCT, are functionally co-existed in cultured HRASMCs.