Anti-TNF-alpha antibody attenuates subarachnoid hemorrhage-induced apoptosis in the hypothalamus by inhibiting the activation of Erk

Abstract

BackgroundSubarachnoid hemorrhage (SAH) can induce apoptosis in many regions of the brain including the cortex and hippocampus. However, few studies have focused on apoptosis in the hypothalamus after SAH. Although some antiapoptotic strategies have been developed for SAH, such as anti-tumor necrosis factor-alpha (TNF-α) antibody, the molecular mechanisms underlying this condition have yet to be elucidated. Therefore, the purpose of this study was to evaluate whether SAH could induce apoptosis in the hypothalamus and identify the potential molecular mechanisms underlying the actions of anti-TNF-α antibody, as a therapeutic regimen, upon apoptosis.Materials and methodsSAH was induced in a rat model. Thirty minutes prior to SAH, anti-TNF-α antibody or U0126, an extracellular signal-regulated kinase (Erk) inhibitor, was microinjected into the left lateral cerebral ventricle. In addition, phorbol-12-myristate-13-acetate was injected intraperitoneally immediately after the anti-TNF-α antibody microinjection. Then, real-time polymerase chain reaction, Western blotting and immunohistochemistry were used to detect the expression of caspase-3, bax, bcl-2, phosphorylated Erk (p-Erk) and Erk. Finally, anxiety-like behavior was identified by using open field.ResultsLevels of caspase-3, bax and bcl-2, all showed a temporary rise after SAH in the hypothalamus, indicating the induction of apoptosis in this brain region. Interestingly, we found that the microinjection of anti-TNF-α antibody could selectively block the elevated levels of bax, suggesting the potential role of anti-TNF-α antibody in the inhibition of SAH-induced apoptosis in the hypothalamus. Moreover, we found that Erk activation was necessary for apoptosis after SAH and that the microinfusion of anti-TNF-α antibody could inhibit apoptosis by suppressing the increase of p-Erk in the hypothalamus. Finally, our data indicated that the infusion of anti-TNF-α antibody could improve anxiety-like behavior.ConclusionCollectively, our data demonstrate that anti-TNF-α antibody attenuates apoptosis in the hypothalamus by inhibiting the activation of Erk, which plays an important role in the treatment of SAH.

Mechanisms and therapeutic implications of RTA 408, an activator of Nrf2, in subarachnoid hemorrhage–induced delayed cerebral vasospasm and secondary brain injury

“…A variety of TNF-α inhibitors have been approved for the treatment of SAH-induced apoptosis. They include anti-tumor necrosis factor-alpha antibody [40], acetylcholine [39], and ethyl pyruvate [41]. We found the treatment with RTA 408 reversed the increased expression of cleaved caspase-3 and TNF-α in the denate gyrus after SAH.…”

“…TNF-α is a pro-inflammatory cytokine involved in neuronal inflammation, apoptosis, and necrosis [39]. TNF-α has been found to be upregulated in both the cerebral cortex and hippocampus in an SAH animal model, and it may be responsible for SAH-induced apoptosis [39][40][41]. A variety of TNF-α inhibitors have been approved for the treatment of SAH-induced apoptosis.…”

GPR18 Agonist Resolvin D2 Reduces the Early Brain Injury in A Rat Model of Subarachnoid Hemorrhage by Multi-Mechanisms of Protection

“…The cerebrospinal uid of SAH patients shows increased TNF levels in platelets and microvessel endothelial cells, suggesting that cerebral vasospasm triggers in ammatory processes that may contribute to brain injury (Eisenhut 2014). SAH-induced neuronal apoptosis can also be alleviated by protecting the BBB (Liu et al 2013) and by delivering anti-TNF-a antibody to the hypothalamus (Ma et al 2018). And hypothalamic in ammation after stroke has been linked to the activity of neuronal POMC and NPY (Pascoal et al 2017).…”

Anti-Cytokine Therapy to Attenuate Ischemic-Reperfusion Associated Brain Injury in the Perinatal Period

“…The generation of mAbs is an effective and specific technique to block signaling pathways activated by a pro-inflammatory cytokine. Previous work has also demonstrated that anti-cytokine therapeutic strategies attenuate the effects of traumatic brain injury [ 88 ], stroke [ 54 ], and subarachnoid hemorrhage [ 89 ] in adult rodents.…”

“…The mAbs were administered as systemic intravenous infusions because this is a clinically relevant route of administration and directly exposes the fetus to the mAb over an extended interval of time. Other routes of administration have previously been used to deliver antibodies directly into the brain via intracerebral injections in experimental studies of adult rodents [ 89 , 93 ]. Intracerebral injections of drugs facilitate the direct entry of drugs into the brain by circumventing the BBB.…”