A decrease in the permeability of aquaporin zero as a possible cause for presbyopia

The crystalline lens appears to be a simple organ with the sole role of focusing light upon the retina. However, numerous studies have underscored its dynamic nature with a host of compartmentalized physiological processes. As the individual ages, the normal lens develops two inescapable processes, presbyopia and cataracts. Yet, to date, there is no uniform explanation for presbyopia and many factors have been proposed as contributors including continuous enlargement of the lens, loss of power of the ciliary muscle and hardening of the lens fibers. Proposed explanations are incomplete and need experimental confirmation. This paper analyzes the possible causes for presbyopia and proposes a new one for it: a decrease in the permeability of aquaporin zero (AQP-0) also known as major intrinsic protein (MIP). Based on original findings of our laboratory, this paper proposes that a fluid flow exists inside the avascular lens. This fluid enters and leaves the lens during the accommodation process. We believe that for this to occur the lens utilizes the permeability of aquaporin zero which is abundant in the membrane of the fiber cells. Volume change due to fluid traversing the surface of the lens occurs during accommodation. We present the hypothesis that increasing the permeability of AQP-0 would facilitate accommodation. Therefore, defects in AQP-0 permeability may be a cause for presbyopia. We would also like to propose that it is possible to visualize and measure the fluid volume lost during un-accommodation and determine if the fluid is lost across the anterior, posterior or both surfaces. An age-related loss in lens water permeability could reduce fluid fluxes during the shape changes of accommodation potentially contributing to presbyopia.Fil: Gerometta, Rosana María del Rosario. Universidad Nacional del Nordeste; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Candia, O.A.. Icahn School of Medicine at Mount Sinai; Estados Unido

Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease

Due to the role of butyrylcholinesterase (BChE)in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE)have been recently envisaged, besides acetylcholinesterase (AChE)inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI)is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl)HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 μM)and selective (>100-fold)inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ)peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001)cell viability when impaired by Aβ1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD. © 2019 Elsevier Masson SA