Melatonin Improves Memory Deficits in Rats with Cerebral Hypoperfusion, Possibly, Through Decreasing the Expression of Small-Conductance Ca2+-Activated K+ Channels
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This study investigated the expression pattern, regulation of expression, and the role of hippocampal small-conductance Ca2+-activated K+ (SK) channels in memory deficits after cerebral hypoperfusion (CHP) with or without melatonin treatment, in rats. Adults male Wistar rats (n = 20/group) were divided into (1) a sham (2) a sham + melatonin (3) a two-vessel occlusion (2-VO) model, and (4) a 2-VO + melatonin. Melatonin was administered (i.p.) to all rats at a daily dose of 10 mg kg−1 for 7 days starting at the time of 2-VO-induction. In contrast to 2-VO rats, melatonin increased the latency of the passive avoidance learning test and decreased time to find the hidden platform in Water Morris Test in all tested rats. In addition, it concomitantly downregulated SK1, SK2, and SK3 channels, downregulated mRNA levels of TNFα and IL-1β, enhanced BDNF levels and activity of PKA levels, and restored the levels of cholinergic markers in the hippocampi of the treated-rats. Mechanistically, melatonin significantly prevented CHP-induced activation of ERK1/2, JNK, and P38 MAPK at least by inhibiting ROS generation and enhancing the total antioxidant potential. In cultured hypoxic hippocampal neurons, individual blockage of MAPK signaling by the MEK1/2 inhibitor (U0126), but not by the P38 inhibitor (SB203580) or JNK inhibitor (SP600125), completely prevented the upregulation of all three kinds of SK channels. These data clearly confirm that upregulation of SK channels plays a role in CHP-induced memory loss and indicate that melatonin reverses memory deficits after CHP in rats, at least by, downregulation of SK1, SK2, and SK3 channels in their hippocampi.
KeywordsMelatonin Cerebral hypoperfusion ERK1/2 SK channels Memory
The authors would like to thank the technical staff of the animal facility at the Medical College of King Khalid University for their help in the experimental procedure and care of animals this study. The authors also would like to express their gratitude to the deanship of scientific research at King Khalid University for their financial support of the current study via their grant to HFS.
HAD, SME, MAK, and HFS conceived and designed the experimental procedures. HAD, HFS, AMH, and MAA performed the experimental procedure and wrote the material and methods. IH, MA, SME, SA and MAA, MD performed the analysis and revised the final version of the manuscript. HAD, MD, and MAA, MAK, and SA were responsible for the interpretation of the results and wrote the manuscript.
This research is fully funded by the deanship of scientific research at King Khalid University (Grant number KKU_S099_33, 2014).
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
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