Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse Models of Dementia

Abstract

The present study was undertaken to explore the potential of erythropoietin in memory deficits of mice. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) and intracerebroventricular streptozotocin (i.c.v STZ, 3 mg/kg, 10 μl, 1 st and 3 rd day) in separate groups of animals. Morris watermaze test was employed to assess learning and memory. The levels of brain thio-barbituric acid reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess degree of oxidative stress. Brain acetylcholinesterase enzyme (AChE) activity was also measured. Scopolamine/streptozotocin administration induced significant impairment of learning and memory in mice as indicated by marked decrease in Morris water-maze performance. Scopolamine/streptozotocin administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (an increase in TBARS and a decrease in GSH) levels. Treatment of erythropoietin (500 and 1,000 IU/Kg i.p.) significantly reversed scopolamine-as well as streptozotocin-induced learning and memory deficits along with attenuation of those-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that erythropoietin exerts a beneficial effect in memory deficits of mice possibly through its multiple actions including potential anti-oxidative effect.

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…Erythropoietin, a glycoprotein hormone that controls erythropoiesis, has been tested in the STZ-icv mice model where the post-treatment with doses of 500 and 1,000 IU/Kg i.p., significantly reversed streptozotocin-induced learning and memory deficits along with attenuation of oxidative stress (TBARS and GSH levels) and restoration of brain AChE activity in the brain (Kumar et al 2010). Similar to that, the antioxidative effect of the HIV protease inhibitor indinavir (100 and 200 mg/kg p.o.…”

“…Many of antioxidant drugs have also been tested in the STZ-icv animal sAD models, suitable for such task due to the chemical nature of STZ which leads to generation of intracellular free radicals, nitric oxide (NO) and hydrogen peroxide, and mitochondrial damage (Szkudelski 2001). In line with that, significant and progressive elevation of MDA and decrement of GSH level, respectively, as well as oxidative-nitrative stress have been found in the rat brain 1 to 8 weeks following the STZ-icv treatment (Sharma and Gupta 2001a;Sharma and Gupta 2002;Ishrat et al 2006;Pathan et al 2006;Shoham et al 2007;Kumar et al 2010;Saxena et al 2011), demonstrating resemblance to the oxidative stress condition in the human sAD patients post-mortem.…”

“…Supporting the hypothesis that the pathophysiology in the STZ-icv animal models shares huge similarities with the one in AD patients, cholinergic deficits have also been consistently found in various STZ-icv animal AD models (from newborn and adult rats to adult mice treated with STZ-icv), by demonstrating as a decrease in ChAT and an increase in AChE activity in the hippocampus, respectively (Hellweg et al 1992;Blokland and Jolles 1993;Blokland and Jolles 1994;Prickaerts et al 1999;Terwel et al 1995;Sonkusare et al 2005;Ishrat et al 2006;(Lester-Coll et al 2006; de la Monte et al 2006;Kumar et al 2010;Tota et al 2011). Importantly, AChE inhibitors tested so far, have been consistently successful in improving/preventing memory deficits in STZ-icv sAD models.…”

“…Following the parenteral administration of high doses, STZ selectively destroys insulin producing/secreting β cells in the pancreas, causing DM type I in adult animals (Szkudelski 2001), while multiple parenteral treatment with low to moderate STZ doses causes insulin resistance by damaging insulin receptor (IR) signalling (Blondel and Portha 1989;Kadowaki et al 1984;Giorgino et al 1992). Intracerebroventricular administration of low, subdiabetogenic doses of STZ has been shown to induce cognitive (Mayer et al 1991;Lannert and Hoyer 1998) and brain cholinergic deficits (Hellweg et al 1992;Blockland andJolles 1993, 1994), oxidative stress (Sharma and Gupta, 2001a;Sharma and Gupta 2002;Ishrat et al 2006;Pathan et al 2006;Shoham et al, 2006;Kumar et al, 2010;Saxena et al, 2011) as well as decrement in brain glucose/energy metabolism (Nitsch and Hoyer 1991;Plaschke et al 1996;Lannert and Hoyer 1998;Hoyer and Lannert 2007), and insulin resistant brain state (Salkovic-Petrisic et al 2006;Gruenblatt et al 2007;Steen 2006;Lester-Coll et al 2006;Agrawal et al 2010). These STZ-icv induced effects have been extensively reviewed elsewhere Salkovic-Petrisic et al 2012), and will not be elaborated here.…”

Neuroprotective effects of erythropoietin on Alzheimer’s dementia model in rats

“…This finding is in accordance with previous studies reporting increased ChAT activity induced by rhEPO in STZ-and lipopolysaccharide-induced sporadic-AD animal models. 25,26 Neuroinflammation is also an important component in the pathogenesis and progression of AD. TNF-α is the major cytokine synthesized by activated microglia and neurons and initiating the inflammatory cascade.…”