Efficacy of a low-dose melatonin pretreatment in protecting against the neurobehavioral consequences of chronic hypoperfusion in middle-aged female rats

Mild cognitive impairment (MCI) is characterized by a reduction in cerebral blood flow. Permanent ligation of the common carotid arteries (2VO) in the rat mimics the chronic decrease in CBF that characterizes aMCI. The current study determined if melatonin (a pineal hormone with neuroprotective properties) can attenuate the neurobehavioral consequences of 2VO using middle-aged female rats. Two weeks following 2VO or sham surgery, rats were tested on various learning and memory tasks. 2VO resulted in hyperlocomotion on the open field. Melatonin attenuated this 2VO-induced hyperactivity. 2VO impaired visual memory however this was not attenuated by melatonin administration. Neither 2VO nor melatonin affected spatial memory performance on the MWM or spatial recognition task. Y-maze testing revealed 2VO rats exhibited a lower spontaneous alternation pattern and performed a greater number of alternate arm returns compared to 2VO rats treated with melatonin. 2VO resulted in a significant loss of CA1 hippocampal neurons which was attenuated with melatonin treatment. Chronic melatonin was found to attenuate the neuronal consequences of chronic cerebral hypoperfusion but only conferred partial behavioral protection in middle-aged female rats. Our results demonstrate that inclusion of older rodents is important in neuroprotection studies as neuroprotective agents may act differently in an aged brain.