Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats

doi:10.1016/j.pbb.2009.09.022

Pharmacology Biochemistry and Behavior

Volume 94, Issue 3, January 2010, Pages 397-403

https://doi.org/10.1016/j.pbb.2009.09.022 Get rights and content

Abstract

In the present study the effect of melatonin on intracerebroventricularly administered streptozotocin (STZ)-induced neurodegeneration was investigated in rats. STZ (3 mg/kg), administered twice with an interval of 48 h between the two doses, showed impairment in spatial memory tested by water maze test after 14 days of 1st dose. Administration of melatonin (2.5, 5.0 and 10 mg/kg, i.p.) was started 1 h prior to 1st dose of STZ and continued up to 14 days. Glutathione and malondialdehyde were used as biochemical markers of oxidative stress in different brain regions. Histopathological changes were examined by using hematoxylin and eosin stain. STZ administration caused significant decrease in glutathione and increase in malondialdehyde as compared to control and artificial Cerebrospinal Fluid treated rats indicating oxidative stress. Brain sections of STZ-treated rats showed increased vacuoles in the periventricular cortical area, damaged periventricular cells and damaged cells in the hippocampal CA4 region as compared to control and artificial Cerebrospinal Fluid treated groups. Melatonin treatment significantly attenuated the effect of STZ-induced oxidative stress and histopathological changes. The results indicate that melatonin is effective in providing protection against memory deficit, oxidative stress and neuronal damage induced by STZ.

Introduction

Melatonin, the primary secretory product of the pineal gland, is a molecule with a great functional versatility. Melatonin has anti-oxidant (free radical scavenging property) which has been linked to its oncostatic, immunomodulatory, and anti-aging properties (Reiter et al., 1997). It has been reported that melatonin levels in Cerebrospinal Fluid (CSF) was significantly decreased in aged individuals with early neuropathological changes in the temporal cortex, and suggested that the decrease in CSF melatonin levels may be an early event in the development of Alzheimer's disease possibly occurring even before the clinical symptoms (Zhou et al., 2003, Feng et al., 2004). Anti-oxidant property of melatonin may play an important role in aging and Alzheimer's disease (Wu and Swabb, 2005). Melatonin is a product that plays not only a major role in the regulation of the circadian rhythms but may also exert neuroprotective effects in Alzheimer's disease (Sanchez-Hidalgo et al., 2008).

Electrophysiological studies have reported that melatonin may regulate the electrical activity of hippocampal neurons (Wang et al., 2005, Musshoff et al., 2002) and alter synaptic transmission between hippocampal neurons (El-Sherif et al., 2003). Melatonin may influence learning and memory process through the synaptic connections within the hippocampus undergoing activity dependent changes in synaptic strength including enhancements in the strength of excitatory synaptic transmission that regulate long term potentiation (Bob and Fedor-Freybergh, 2008).

Experimental studies in rodent models also demonstrated effectiveness of melatonin on memory improvement (Gonzalez-Burgos et al., 2007). In the present study, we used the intracerebroventricular (ICV) administered streptozotocin (STZ), a glucosamine derivative of nitrosourea, induced model of dementia in rats which is based on the generation of free radicals in the brain (Sharma and Gupta, 2001a, Sharma and Gupta, 2001b). STZ in subdiabetogenic dose in rats causes prolonged impairment of brain glucose and energy metabolism, decreased choline acetyltransferase levels in the hippocampus, and generation of free radicals in the brain accompanied by impairment in learning and memory (Lannert and Hoyer, 1998). The previous studies also demonstrated the effectiveness of melatonin in preventing the cognitive deficits as well as the oxidative stress caused by STZ in rats (Sharma and Gupta, 2001a, Sharma and Gupta, 2001b). However, potential of melatonin against histopathological changes induced by ICV injection of STZ was not evaluated. Therefore, we thought that it would be worthwhile to correlate the effect of melatonin on behavioral and biochemical markers of oxidative stress, i.e. glutathione (GSH) and malondialdehyde with histopathological changes in the brain of STZ-treated rats.

Section snippets

Animals

The experiments were carried out with adult male Sprague Dawley rats weighing 250–280 g (14–16 weeks). The animals were kept in a polyacrylic cage (22.5 × 37.5 cm) with 5 rats per cage and maintained under standard housing conditions (room temperature 24–27 °C and humidity 60–65%) with a 12-h light and dark cycle. Food, in the form of dry pellets, and water were available ad libitum but food was not allowed during experiments (approximate 1–2 h). The animals were procured from the Laboratory Animal

Effect of different doses of melatonin on STZ-induced memory deficits in Morris water maze test

In control and CSF groups latency times in the 2nd and 3rd retention sessions were significantly lower than in the 1st session [control group: F (2, 12) = 24.59, CSF group: F (2, 12) = 413.49, P < 0.001]. There was no significant change in latency to reach the platform in STZ-treated rats in retention sessions (2nd and 3rd) in comparison to the 1st session [F (2, 12) = 0.8313, P > 0.05]. Daily treatment with melatonin was started from the day of first ICV injection of STZ in three different doses i.e. 2.5

Discussion

The present study was designed to provide histopathological evidence for neuroptotective activity of melatonin along with memory improvement and anti-oxidant effect against neuronal damage caused by STZ given by ICV route in brain areas. Memory deficit induced by STZ in Morris water maze test in rats is a commonly used rodent model of dementia. STZ causes neuronal damage in the brain by producing free radicals, thereby inducing the state of oxidative stress, impairment of glucose utilization

Acknowledgement

The authors express their gratitude to Dr. Venkatesh Prasuja for his help in histopathological studies and GS is grateful to the Indian Council of Medical Research for fellowship.

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Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats☆

Abstract

Introduction

Section snippets

Animals

Effect of different doses of melatonin on STZ-induced memory deficits in Morris water maze test

Discussion

Acknowledgement

Pharmacol Biochem Behav

Arch Biochem Biophys

Neurosci Lett

J Neurol Sci

Life Sci

Pharmacol Biochem Behav

Life Sci

Pharmacol Biochem Behav

Life Sci

Exp Neurol

Melatonin, consciousness, and traumatic stress

J Pineal Res

Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis

J Cereb Blood Flow Metab