Prophylactic Subacute Administration of Zinc Increases CCL2, CCR2, FGF2, and IGF-1 Expression and Prevents the Long-Term Memory Loss in a Rat Model of Cerebral Hypoxia-Ischemia

Abstract

Prophylactic subacute administration of zinc decreases lipoperoxidation and cell death following a transient cerebral hypoxia-ischemia, thus suggesting neuroprotective and preconditioning effects. Chemokines and growth factors are also involved in the neuroprotective effect in hypoxia-ischemia. We explored whether zinc prevents the cerebral cortex-hippocampus injury through regulation of CCL2, CCR2, FGF2, and IGF-1 expression following a 10 min of common carotid artery occlusion (CCAO). Male rats were grouped as follows: (1) Zn96h, rats injected with ZnCl2 (one dose every 24 h during four days); (2) Zn96h + CCAO, rats treated with ZnCl2 before CCAO; (3) CCAO, rats with CCAO only; (4) Sham group, rats with mock CCAO; and (5) untreated rats. The cerebral cortex-hippocampus was dissected at different times before and after CCAO. CCL2/CCR2, FGF2, and IGF-1 expression was assessed by RT-PCR and ELISA. Learning in Morris Water Maze was achieved by daily training during 5 days. Long-term memory was evaluated on day 7 after learning. Subacute administration of zinc increased expression of CCL2, CCR2, FGF2, and IGF-1 in the early and late phases of postreperfusion and prevented the CCAO-induced memory loss in the rat. These results might be explained by the induction of neural plasticity because of the expression of CCL2 and growth factors.

Prophylactic Zinc and Therapeutic Selenium Administration Increases the Antioxidant Enzyme Activity in the Rat Temporoparietal Cortex and Improves Memory after a Transient Hypoxia‐Ischemia

“…The facilitation of learning and improvement of cognitive development have been associated to the neuroprotective effect of zinc, which decreases free radicals produced by cerebral ischemia [ 76 ]. Our group showed similar results in the preconditioning effect of subacute zinc administration in the CCAO rat model [ 5 ]. However, the prophylactic chronic zinc administration (0.2 mg/kg of body weight/days) exerted a partial effect because there was no memory consolidation as reported previously with a higher dose of zinc [ 19 ].…”

“…Furthermore, CCL2 also stimulates the migration of neuronal precursor cells to the damaged area [ 66 ]. We have previously reported that high levels of CCL2 by a subacute prophylactic administration of zinc are associated with a preconditioning process [ 5 ]. However, the combined treatment with zinc and selenium did not maintain the preconditioning effect of zinc but exerted the therapeutic effect of selenium in the late phase.…”

“…Several mechanisms can be accounted for the latter effect. For instance, the decrease in interleukin-1 (IL-1) and IL-23 expression [ 4 ], increase in chemokine and growth factor levels [ 5 ], and decrease in oxidative stress are because of the antioxidant activity of Cu and Zn superoxide dismutase (SOD1 and 3) [ 6 ]. However, excessive accumulation of zinc can also cause neuronal degeneration in the hippocampus and cerebral cortex [ 7 ].…”

“…Our group has reported opposite effects of zinc administration in the 10 min common carotid artery occlusion (CCAO) rat model, where CCAO causes cell death by apoptosis and necrosis without producing an ischemic core [ 11 , 18 ]. The subacute administration of zinc (2.5 mg/kg) before CCAO exerts a neuroprotective effect by increasing the expression of CCL2/CCR2, FGF2, and IGF-1 in the temporoparietal rat cortex [ 5 ]. In contrast, chronic zinc administration at a low dose (0.5 mg/kg body weight) before CCAO decreases CCL2/CCR2, CCL3/CCR1, CCL4/CCR8, and CXCL13/CXCR5 and increases CXCL12/CXCR4, but does not prevent cell death in the late phase [ 19 ].…”

A distinct pattern of sterile inflammation induced by zinc oxide nanowires.

“…CCL2 levels after ZnONP exposure either in vivo (lung) or in vitro[158,179,214]. According to Sahu et al, ZnONP promote the expression of the MCP-1 mRNA level in THP-1 cells in vitro after exposure[215].…”