Abstract
Administration of streptozotocin (STZ) through intracerebroventricular (ICV) route manifests AD symptoms in rats. STZ deregulates the control over GSK-3 and eNOS activities through disruption of phosphoinositides mediated signaling. We attempted to elucidate the functions of GSK-3 and eNOS in memory enhancing activity of ellagic acid (EGA) in STZ (ICV) triggered AD type dementia. A 3 mg/kg dose of STZ was injected gently in lateral cerebral ventricles of rats on day 1 and 3. The rats were given EGA (35 mg/kg b.w.) through oral route for four weeks daily. LiCl (GSK-3 inhibitor) and L-Arginine (NO precursor) were administered for four weeks to explore the modulation of GSK-3 and eNOS respectively by EGA in STZ (ICV) injected rats. MWM and EPM paradigms were utilized for evaluation of memory of rats. The rats were sacrificed on day 28 to determine markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, LDH, TNF-α and eNOS in brain. STZ (ICV) initiated cognitive deficits through enhancement of brain oxidative stress, nitrite, TNF-α, AChE, LDH activity and reduction in eNOS levels. EGA attenuated the rise in oxidative stress, inflammation and LDH activity in STZ (ICV) treated rats. Decrease in nitrite content, AChE activity and resurrection of eNOS activity by EGA averted STZ (ICV) induced memory dysfunction in rats. Chronic inhibition of GSK-3 by LiCl (100 mg/kg, i.p.) enhanced these effects of EGA in STZ (ICV) injected rats which thereby exhibited marked cognitive improvement. L-Arginine group manifested inflation in brain oxidative stress, TNF-α content, AChE and LDH activities. L-Arginine (200 mg/kg, i.p.) surged the nitrite content even though eNOS expression was diminished in brain of EGA and STZ (ICV) administered rats resulting in profound loss of memory. It can be concluded that GSK-3 and eNOS are involved in memory enhancing activity of EGA in STZ (ICV) injected rats.
Highlights
Ellagic acid (EGA) constitutes natural polyphenol in nuts, pomegranates, berries and beverages[1]
We propose that suppression of GSK-3 overactivity and resurrection of endothelial nitric oxide synthase (eNOS) activity in brain of rats is involved in prevention of memory loss by EGA in STZ group. (STZ) (ICV) model
LiCl and L-Arginine modulate the impact of EGA on memory of STZ (ICV) treated rats in Morris water maze (MWM)
Summary
Ellagic acid (EGA) constitutes natural polyphenol in nuts, pomegranates, berries and beverages[1]. EGA enriched dietary supplements (e.g. PomActivTM) enjoy wide popularity owing to its potent antioxidative, anti-inflammatory, vasorelaxing, hypolipidemic, antidiabetic and antitumor properties[2]. A clinical study revealed upper GIT as major site of absorption of EGA with extensive in vivo protein binding and intestinal transformation[3].
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