Neuroprotection of Ischemic Preconditioning is Mediated by Anti-inflammatory, Not Pro-inflammatory, Cytokines in the Gerbil Hippocampus Induced by a Subsequent Lethal Transient Cerebral Ischemia

Abstract

Ischemic preconditioning (IPC) induced by sublethal transient cerebral ischemia could reduce neuronal damage/death following a subsequent lethal transient cerebral ischemia. We, in this study, compared expressions of interleukin (IL)-2 and tumor necrosis factor (TNF)-α as pro-inflammatory cytokines, and IL-4 and IL-13 as anti-inflammatory cytokines in the gerbil hippocampal CA1 region between animals with lethal ischemia and ones with IPC followed by lethal ischemia. In the animals with lethal ischemia, pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region were dead at 5 days post-ischemia; however, IPC protected the CA1 pyramidal neurons from lethal ischemic injury. Expressions of all cytokines were significantly decreased in the SP after lethal ischemia and hardly detected in the SP at 5 days post-ischemia because the CA1 pyramidal neurons were dead. IPC increased expressions of anti-inflammatory cytokines (IL-4 and IL-13) in the stratum pyramidale of the CA1 region following no lethal ischemia (sham-operation), and the increased expressions of IL-4 and IL-13 by IPC were continuously maintained is the SP of the CA1 region after lethal ischemia. However, pro-inflammatory cytokines (IL-2 and TNF-α) in the SP of the CA1 region were similar those in the sham-operated animals with IPC, and the IL-4 and IL-13 expressions in the SP were maintained after lethal ischemia. In conclusion, this study shows that anti-inflammatory cytokines significantly increased and longer maintained by IPC and this might be closely associated with neuroprotection after lethal transient cerebral ischemia.

Experimental Pretreatment with Chlorogenic Acid Prevents Transient Ischemia-Induced Cognitive Decline and Neuronal Damage in the Hippocampus through Anti-Oxidative and Anti-Inflammatory Effects

“…Since the brain is well known to be an aseptic organ, and pathogens are not involved in the neuroinflammatory response following ischemia-reperfusion injury, some studies call this response a “sterile inflammatory response” [ 46 , 48 ]. In addition, neuroinflammation is concerned with both beneficial and detrimental roles in ischemic brains, and these are modulated by anti- and pro-inflammatory cytokines [ 49 , 50 , 51 ]. It is well known that pro-inflammatory cytokines exacerbate and advance deleterious inflammatory processes, but anti-inflammatory cytokines suppress the expressions of pro-inflammatory cytokines and bring advantageous inflammatory processes in ischemic brains [ 10 , 52 ].…”

Pre-treatment with Chrysanthemum indicum Linné extract protects pyramidal neurons from transient cerebral ischemia via increasing antioxidants in the gerbil hippocampal CA1 region

“…It has been reported (6,29) that pyramidal cells of the stratum pyramidale in the hippocampal CA1 region die several days following transient cerebral ischemia. Mongolian gerbils have been generally used as a good experimental animal model of transient cerebral ischemia as the posterior communicating arteries in Willis' circle, which connect the vertebrabasilar and carotid arterial system, are lacking in gerbils and transient cerebral ischemia can easily be made by the ligation of bilateral common carotid arteries (24,30,31). …”

“…As previously described (24), gerbils (n=7 at each time point in each group) were anesthetized with pentobarbital sodium at the designated times and perfused transcardially with 0.1 M phosphate-buffered saline (pH 7.4) followed by 4% paraformaldehyde in 0.1 M phosphate-buffer (PB; pH 7.4). The brains were removed and postfixed in the same fixative for 6 h, and the brain tissues were sectioned on a cryostat (Leica Microsystems GmbH, Wetzlar, Germany) into 30 µm coronal sections.…”

“…Immunohistochemistry was performed according to the previously published procedure (24). In short, the sections were incubated with diluted mouse anti-neuronal nuclei (NeuN; 1:800; cat.…”

Immune System Involvement in the Degeneration, Neuroprotection, and Restoration after Stroke

“…"mong the activated mechanisms are an increase in anti-inlammatory cytokines such as IL-4 and IL-13 that ease hippocampal pyramidal neuron survival after an ischemic event in gerbils [90]. Tu XK and his team also demonstrated that neuroprotection can be originated by pre-conditioning through modulation of the phosphatidyl inositol 3-kinase PI3K/"kt and ERK1/2 pathway modulation [91] CD3, CD8 T cells.…”