Inhibition of Peripheral TNF-α and Downregulation of Microglial Activation by Alpha-Lipoic Acid and Etanercept Protect Rat Brain Against Ischemic Stroke

Abstract

Ischemic stroke, caused by obstruction of blood flow to the brain, would initiate microglia activation which contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation could be a therapeutic strategy for ischemic stroke. This study was aimed to elucidate the anti-inflammatory effects of alpha-lipoic acid and etanercept given either singly or in combination in rats subjected to middle cerebral artery occlusion. Both α-lipoic acid and etanercept markedly reduced cerebral infarct, blood-brain barrier disruption, and neurological motor deficits with the former drug being more effective with the dosage used. Furthermore, when used in combination, the reduction was more substantial. Remarkably, a greater diminution in the serum levels of tumor necrosis factor-alpha as well as the brain levels of microglial activation (e.g., microgliosis, amoeboid microglia, and microglial overexpression of tumor necrosis factor-α) was observed with the combined drug treatment as compared to the drugs given separately. We conclude that inhibition of peripheral tumor necrosis factor-alpha as well as downregulation of brain microglial activation by alpha-lipoic acid or etanercept protect rat brain against ischemic stroke. Moreover, when both drugs were used in combination, the stroke recovery was promoted more extensively.

α-Lipoic Acid Promotes Neurological Recovery After Ischemic Stroke by Activating the Nrf2/HO-1 Pathway to Attenuate Oxidative Damage

“…In the study of Wu et al [36], the neuroportective of α-LA was attributed to inhibition of peripheral tumor necrosis factor-alpha and downregulation of brain microglial activation. In another research, the effect of α-LA was partially attributed to activation of insulin receptor because HNMPA-(AM)3, an insulin receptor inhibitor, blocked the neurorestorative effects of α-LA [12].…”

“…Previous studies about the regulation of lipoic acid on ischemic stroke have been reported in animal models [11, 12] and in clinical study [13]. The cellular and molecular mechanisms associated with the protective effects of LA in ischemic stroke are partially be attributed to downregulation of microglial activation [11] and activation of insulin receptor [12]. In addition, LA attenuates cardiomyoctyes necrosis and apoptosis by activating the PI3K/Akt pathway as well as subsequent Nrf2 and HO-1 in experimental animal models of myocardial ischemia [14].…”

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…As reviewed by Pan and Kastin (2007), TNF-α was shown to have both detrimental and beneficial effects in stroke [121]. Several studies reported that inhibition of TNF-α (e.g., by etanercept, a human TNFR2-IgG Fc fusion protein) reduces infarct size and neuroinflammation [122][123][124][125], while, on the other hand, complete knockout of both TNFRs increases the sensitivity for stroke and aggravates neuronal damage [5]. Moreover, in stroke in vitro and animal models, pre-treatment with TNF-α (which models ischemic preconditioning) mediates neuroprotective effects after ischemia [126,127].…”

“…Moreover, it may be that certain compounds, in certain conditions, do not necessarily have to pass the BBB to reach therapeutic effects. For example, in rat MCAO models for cerebral ischemia beneficial effects were reported upon intraperitoneal injection of etanercept [124,125]. However, it may be that etanercept could enter the brain via disruptions in the BBB, induced by the MCAO [124].…”

“…For example, in rat MCAO models for cerebral ischemia beneficial effects were reported upon intraperitoneal injection of etanercept [124,125]. However, it may be that etanercept could enter the brain via disruptions in the BBB, induced by the MCAO [124]. Other important issues that will need to be addressed include the timing of treatment, and the potential side-effects that may arise from targeting TNF-α, TNFR1, and/or TNFR2.…”