Exercise Therapy Downregulates the Overexpression of TLR4, TLR2, MyD88 and NF-κB after Cerebral Ischemia in Rats

Abstract

Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) are considered to mediate the inflammatory reaction of cerebral ischemia injury, and exercise can inhibit the activity of the Toll-like receptor signaling pathway in the peripheral blood of humans. Although physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings, the underlying mechanism remains unclear. To clarify this critical issue, this study investigated the effects of treadmill training on the recovery of neurological function and the expression of TLR2 and TLR4 and their main downstream targets, nuclear factor-kappaB (NF-κB) and myeloid differentiation factor 88 (MyD88), in the ischemic rat brain after middle cerebral artery occlusion-reperfusion (MCAo/R). Rats were divided into seven groups: sham control without MCAo/R and five, nine and 16 days post-ischemic exercise or non-exercise. The neurological function and infarct volume were measured, and reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression of TLR2, TLR4, NF-κB and MyD88 in ischemic brain tissue. The results indicated that treadmill training promoted functional recovery and reduced the overexpression of TLR2, TLR4, NF-κB and MyD88 in rat brain tissue after ischemia, a finding that may have implications for understanding the mechanism of exercise therapy after brain ischemia and indicating new therapeutic strategies for the pharmacological modulation of TLR signaling.

Electroacupunctre improves motor impairment via inhibition of microglia-mediated neuroinflammation in the sensorimotor cortex after ischemic stroke

“…There is increasing evidence that p38 MAPK play a role in microglia/macrophages-mediated neuroinflammation, could lead to positively regulate transcription of inflammatory genes, such as TNFa, IL-1β following ischemic stroke [64][65]. It would be noteworthy that inhibitions of p38 MAPK-, MyD88-and NF-κB-mediated signaling pathway could decrease the microglia-mediated neuroinflammation following ischemia and reperfusion [63,65].The present study demonstrated that EA treatment prevented from the nuclear translocation of NF-κB p65 following MCAO/R injury and suppressed the expression of p38 MAPK and MyD88 accompanied by the decrease of IL-1β, IL-6 and TNF-α in the peri-infarct sensorimotor cortex.…”

“…The further study elucidated the possible mechanisms of antiinflammation involved. Previous studies have suggested that activated microglia increased the production of proinflammatory cytokines through activation of the NF-κB-or p38 MCAK-or MyD88-mediated signaling in vivo or in vitro [9,[59][60][61][62][63]. Sensors of the innate immune system, such as Toll-like receptors (TLRs), mediated MyD88-dependent pathway to activate NF-κB, which induces the expression of proinflammatory genes, inflammatory cytokines and the activation of adaptive immunity [60].…”

Treadmill exercise promotes neuroprotection against cerebral ischemia–reperfusion injury via downregulation of pro-inflammatory mediators

“…Schimidt et al37 demonstrated that physical exercise attenuated oxidative stress and promoted better neuroprotection to an ischemic event. Ma et al’s38 results indicated that exercise therapy downregulated the overexpression of toll-like receptors after cerebral ischemia. These studies showed the beneficial role of exercise through different mechanisms.…”

“…Increasing evidences have demonstrated that inflammation resulted from leukocyte infiltration via reperfusion may play an important role in the pathogenesis of ischemic stroke 11,38. During brain Ischemia–reperfusion injury, pro-inflammatory mediators such as IL-1β, TNF-α, and MCP-1 are produced by microglia/macrophages and astrocytes,39 which are believed to contribute to ischemic stroke 40.…”

Toll-like receptor 4 is associated with seizures following ischemia with hyperglycemia

“…Neurological outcomes after cerebral infarction are improved in mice with a TLR4 deficiency (Cao et al, 2007;Hua et al, 2007). Exercise therapy, electroacupuncture and certain medicines may play a protective role against ischemic injury via the downregulation of TLR4 expression (Ajamieh et al, 2012a, b;Suzuki et al, 2012;Lan et al, 2013;Ma et al, 2013). Both in vivo and in vitro studies have demonstrated that hyperglycemia activates TLR4 expression and exacerbates the inflammatory response (Devaraj et al, 2009;Amir et al, 2011;Kaur et al, 2012).…”