Overexpression of hsp27 Rescued Neuronal Cell Death and Reduction in Life- and Health-Span in Drosophila melanogaster Against Prolonged Exposure to Dichlorvos

Abstract

Long-term exposure to dichlorvos (O,O-dimethyl-2,2-dichlorovinyl phosphate (DDVP), an organophosphate pesticide) is reported to exert neurotoxicity, i.e., generation of reactive oxygen species (ROS), oxidative damage, and neuronal cell death along with life- and health-span reduction in nontarget organisms including humans. However, studies on genetic modulation towards neuroprotection against prolonged DDVP exposure are elusive. Hsp27 (a small heat shock protein) is involved in various cellular processes and thus has attained emphasis as a therapeutic target. We aimed to examine the protective effect of hsp27 overexpression against prolonged DDVP exposure using an in vivo model Drosophila melanogaster. Flies were exposed to 15.0 ng/ml DDVP for a prolonged period to examine neuronal cell death, locomotor performance, and lifespan. After prolonged exposure, cell death, ROS level, glutathione depletion, nicotinamide adenine dinucleotide phosphate level (NADPH), glucose-6-phosphate dehydrogenase (G6PD), and thioredoxin reductase (TrxR) activities were examined in fly brain tissues at different days of age (days 10, 20, and 30). Flies with ubiquitous overexpression of hsp27 showed better resistance (improved lifespan and locomotor performance) in comparison to that targeted to motor neurons and nervous system. These flies also exhibited lesser intracellular ROS level and glutathione depletion by restoring G6PD activity, NADPH level, and TrxR activity in their brains thereby resisted neuronal cell death. Conversely, hsp27 knockdown flies exhibited reversal of the above endpoints. The study evidenced the neuroprotective efficacy of hsp27 overexpression against prolonged DDVP exposure and favored Hsp27 as a therapeutic target towards achieving better organismal (including human) health against long-term chemical exposure.

HSP27 Inhibits Homocysteine-Induced Endothelial Apoptosis by Modulation of ROS Production and Mitochondrial Caspase-Dependent Apoptotic Pathway

“…HSP27 in atherosclerotic plaques diminishes with progression of the stage of the pathology [ 15 , 16 ] and is thereby viewed as a potential biomarker [ 14 ]. It has also been shown that HSP27 can protect cells from apoptosis induced by various stimuli in vivo and in vitro [ 17 – 20 ]. This cytoprotective effect of HSP27 is associated with decrease in ROS [ 21 ] and increase in glutathione [ 22 ] during oxidative stress.…”

Protective Role of Hsp27 in the Nonylphenol-Induced Locomotory and Longevity Toxicity

“…For example, previous studies have shown that overexpression of Hsp27 in the brain ameliorates symptoms of neurological diseases. 17 29…”

“…16 Moreover, Drosophila has been previously used to understand the link between Hsp27 , aging, and locomotory behavior. 17 The European Centre for the Validation of Alternative Methods (ECVAM) recommends Drosophila as an alternative model that follows the 3R rule, i.e., reducing, refining, and replacing the use of laboratory animals. 18…”

Ayurvedic Amalaki Rasayana promotes improved stress tolerance and thus has anti-aging effects in Drosophila melanogaster

“…On the other hand we found that basal as well as heat shock induced levels of Hsp27 were significantly more elevated in AR fed larvae. It is interesting that although Hsp27 is reported to be unessential for surviving heat shock (Hao et al 2007), it plays significant roles in tolerance to other insults like starvation, oxidative stress etc and also in determining the life span of flies (Hao et al 2007, Pandey et al 2015Shi et al 2011;Wang et al 2004). Thus, the improved thermo-tolerance of AR fed larvae and flies does not appear to be due to their stronger heat shock response.…”