Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that belongs to the phosphoinositide kinase-related kinase family (PIKK family) and is a downstream effector of the PI3K/PKB (protein kinase B) signaling pathway. mTOR plays important roles in transcription, protein translation, apoptosis, and actin cytoskeleton organization.

The interaction of mitogens with their receptors leads to activation of PI3K, which converts PIP2 into PIP3. PIP3 directly interacts with the PH domain of AKT, thus leading to its membrane translocation and activation. Tuberin, the heterodimer consisting of tuberous sclerosis complex 1 and 2 (TSC1/2), is a substrate of AKT and a negative regulator of the mTOR signaling pathway. Tuberin converts the active GTP-bound Rheb into the inactive GDP-bound form of Rheb. Rheb is an upstream regulator of mTOR that directly binds to the mTOR kinase domain and changes the conformation of mTOR-Raptor complex to activate mTOR kinase activity [21].

Studies have shown that the mTOR pathway plays an important role in cerebral ischemia and also in neuronal autophagy and apoptosis. Currently, mTOR is believed to play a dual role in post-SAH EBI. Zhang et al. [24] found that the mTOR signaling pathway also plays an important role in cerebral vasospasm after SAH. They examined expression levels of several important components of the mTOR signaling pathway after SAH, including mTOR and P70S6K1. In addition, they also investigated the effects of the mTOR inhibitors rapamycin and AZD8055 on basilar artery after SAH and on the expression levels of mTOR and P70S6K1. Their results showed that, after SAH, activation of the mTOR pathway may promote proliferation of vascular smooth muscle, and thus is involved in the regulation of vasospasm of the basilar artery. The application of the mTOR inhibitors rapamycin and AZD8055 can significantly relieve arterial spasticity.

The mTOR pathway and mTOR inhibitors have become the focus of intensive research. These studies will likely help us to better understand EBI and CVS after SAH and could provide new ideas for intervention in the progression of EBI after SAH.

Toll-like receptors (TLRs) are a class of innate immune receptors initially discovered in Drosophila. TLRs are expressed in many immune cells, including macrophages, dendritic cells, lymphocytes, and natural killer cells. They play a key role in the immune response. At least 12 TLR receptors have been identified, among which TLR4 is the main receptor for endotoxin/LPS (lipopolysaccharide) [18].

Ligand binding triggers signal transduction of the TIR region of TLR4 and activation of the nuclear factor κB (NF-κB) pathway and mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting the expression of various inflammatory cytokines. NF-κB can be activated by a variety of inflammatory substances and also by oxidative stress to promote transcription of a plethora of genes that play important roles in the immune response and tissue damage response.

Toll receptors act through an intracellular signaling cascade to activate the inflammation-related MAPK pathway and NF-κB signaling pathway. Activated NF-κB enters the nucleus to promote the transcription of inflammatory cytokines, including IL-1β, TNF-α, IL-6, ICAM-1, and MCP-1. Furthermore, NF-κB is closely related to apoptosis pathways; NF-κB can inhibit the caspase family, therefore inhibiting neuronal apoptosis after EBI. However, NF-κB also stimulates the expression of TNF-α, thus inducing apoptosis. Thus, NF-κB is a key factor in regulating post-EBI inflammation and neuronal apoptosis. Caspase signaling and MAPK signaling pathways are also important to EBI after SAH, as treatment with the caspase inhibitor z-VAD-FMK or MAPK inhibitor PP1 can significantly mitigate symptoms of EBI [12].

Sun et al. [20] showed that the TLR/NF-κB signaling pathway is involved in the inflammatory response in EBI after SAH and that tamoxifen can protect the brain from EBI after SAH by effectively inhibiting the expression of TLR4, NF-κB, and some other downstream inflammatory mediators (IL-1β, TNF-α, IL-6, etc.). They further confirmed that the use of tamoxifen can improve neurological cognition of SAH patients. Wang et al. [23] also confirmed the important role of the TLR4 pathway in post-SAH EBI and further showed that melatonin treatment can protect the brain and improve cognitive function of patients.