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. 2022 Apr;29(4):2958-2968.
doi: 10.1016/j.sjbs.2022.01.018. Epub 2022 Jan 18.

Melatonin attenuates cerebral hypoperfusion-induced hippocampal damage and memory deficits in rats by suppressing TRPM7 channels

Hussain Al Dera  1 , Mohammed Alassiri  2 , Reem Al Kahtani  1 , Samy M Eleawa  3 , Mohammad K AlMulla  3 , Abdulhakeem Alamri  4
Affiliations

Melatonin attenuates cerebral hypoperfusion-induced hippocampal damage and memory deficits in rats by suppressing TRPM7 channels

Hussain Al Dera et al. Saudi J Biol Sci. 2022 Apr.

Abstract

This study was conducted to examine if modulating transporters like transient receptor potential cation channels, subfamily M, member 7 (TRPM7) underlies the hippocampal neuroprotection afforded by melatonin (Mel) in rats exposed to cerebral hypoperfusion (CHP). Experimental groups included control, Mel-treated (1.87 g/kg), CHP, and CHP + Mel (1.87 g/kg)-treated rats. CHP was induced by the permanent bilateral occlusion of the common carotid arteries (2VO) method and treatments were conducted for 7 days, orally. Mel prevented the damage of the dental gyrus and memory loss in CHP rats and inhibited the hippocampal reactive oxygen species (ROS), lipid peroxidation levels of tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), interleukine-1 beta (IL-1β), and prostaglandin E2 (PGE2). It also reduced the hippocampal transcription of the TRPM7 channels and lowered levels of calcium (Ca2+) and zinc (Zn2+). Mel Also enhanced the levels of total glutathione (GSH) and superoxide dismutase (SOD) in the hippocampus of the control and CHP-treated rats. In conclusion, downregulation of TRPM7 seems to be one mechanism underlying the neuroprotective effect of Mel against global ischemia and is triggered by its antioxidant potential.

Keywords: Calcium; Cerebral hypoperfusion; Hippocampus; Ischemia; Melatonin; Memory; Oxidative stress; TRPM7.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Melatonin improves spatial memory function in CHP-model rats. A and B: Represent the escape time intervals and their area under the curve to find the hidden base. C: Represents the average number of crossing times during the probe trial. All data are presented as means ± SD (n = 10 rats/group). ***: p < 0.0001 vs. sham-operated rats. ###: p < 0.0001 vs. Mel-treated rats. $$$: p < 0.0001 vs. rats with cerebral hypoperfusion (CHP).
Fig. 2
Fig. 2
Melatonin (Mel) suppresses oxidative stress and enhances antioxidant levels in the hippocampi of CHP rats. All data are presented as means ± SD (n = 10 rats/group) *,**,***: p < 0.05, 0.01, and 0.0001, respectively vs. sham-operated rats. ##,###: p < 0.01 and 0.0001, respectively Vs. Mel-treated rats. $$$: p < 0.0001 vs. CHP-induced rats.
Fig. 3
Fig. 3
Melatonin (Mel) suppresses inflammation in the hippocampi of CHP-induced rats. All data are presented as means ± SD (n = 10 rats/group). **,***: p < 0.01, and 0.0001, respectively vs. sham-operated rats. ##,###: p < 0.01 and 0.0001, respectively Vs. Mel-treated rats. $$$: p < 0.0001 vs. CHP-induced rats.
Fig. 4
Fig. 4
Melatonin (Mel) reduces the elevation in intracellular Zn+2 and Ca + 2 levels in the hippocampi of CHP-induced rats which are positively correlated with the intracellular levels of ROS All data are presented as means ± SD (n = 10 rats/group). *,**,***: p < 0.05, 0.01, and 0.0001, respectively vs. sham-operated rats. ##,###: p < 0.01 and 0.0001, respectively vs. Mel-treated rats. $$$: p < 0.0001 vs. CHP-induced rats.
Fig. 5
Fig. 5
Melatonin (Mel) downregulates TRMP7 in the hippocampi of CHP-induced rats which are positively correlated with the intracellular levels of Zn+2 and Ca + 2 levels. All data are presented as means ± SD (n = 10 rats/group). ***: p < 0.0001 vs. to sham-operated rats (lane 1). ###: p < 0.0001, respectively vs. Mel-treated rats (lane 2). $$$: p < 0.0001 vs. CHP-induced rats (lane 3). Lane 4: CHP + Mel.
Fig. 6
Fig. 6
Histological micrographs obtained from rat dental gyrus (DG) hippocampus (CA1 region) stained by H&E. 200X. A&B: represents control and Mel-treated rats, demonstrating a normal number of cell layers in the glandular layer of the DG with intact cells containing normally rounded nuclei (Long arrow). C: represents CHP-induced rats and showed an obvious reduction in the number of cells (layers) forming the glandular layer of the DG hippocampal area (short arrow) with many pyknotic apoptotic nuclei (long arrow). D: represents CHP + Mel-treated rats and shows normal DG structure similar to the control rats (long arrow).
Fig. 7
Fig. 7
Transmission electron micrographs (TEM) of the neuron in the hippocampus of rats. (X5000). A & B: represent control and Mel-treated rats, respectively, and show normal hippocampus neurons containing normally rounded nuclei (N), intact mitochondria (m) with double membranes, normal rough endoplasmic reticulum (RER), and. Also, note the presence of intact synapses (S). C: represents CHP-induced rats and showed apoptotic hippocampus neurons with clear damage in the mitochondria (m), apoptotic nuclei (N), and pleomorphic disturbed RER, (X5000). D: represents CHP + Mel-treated rats and showing intact with partially changed hippocampus neuron with normally appeared organelle and clear synapse.
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