NSCs can proliferate, migrate and differentiate into neurons, astrocytes and/or oligodendrocytes. During the pathological process, NSCs can proliferate, migrate to lesions and rebuild the damaged neuronal network in response to extracellular signal changes. It was reported that stable analogs of LXA₄ and ATLA₄ could directly regulate the growth of NSCs isolated from embryonic mouse brains by improving growth-related gene expression, including epidermal growth factor receptor, cyclin E, p27, and caspase 8 (Wada et al., 2006). Another study demonstrated that FPR2/ALX detected in NSCs can promote NSC migration through F-actin polymerization and skew NSC differentiation to neurons, implying that LXs may serve as candidates for the treatment of brain or spinal cord injury (Wang et al., 2016).

The protective effects of LXs on neurons have also been extensively studied. LXs can reduce neuronal death in response to a variety of stimuli, including staurosporine, glutamate, paraquat, serum deprivation and oxygen-glucose deprivation (Zhu et al., 2016; Livne-Bar et al., 2017; Zhu et al., 2020), which has been explained to be related to their anti-inflammatory, anti-apoptotic and antioxidative effects (Zhu et al., 2016; Zhu et al., 2020). Furthermore, FPR2/ALX mediated axonal and dendritic outgrowth, suggesting that LXs may promote neuronal repair by activating FPR2/ALX (Ho et al., 2018).

Microglia are the resident immune cells of the CNS. They are activated in response to pathological insults and harmful stimuli, a process termed polarization. Activated microglia have been largely classified into two phenotypes, namely, classically activated (M1, proinflammatory) or alternatively activated (M2, anti-inflammatory) microglia. Proinflammatory microglia produce inflammatory mediators and exert detrimental effects. Conversely, anti-inflammatory microglia phagocytose cell fragments, dampen the inflammatory response and promote tissue repair. A study demonstrated that proinflammatory microglia could downregulate their capacity to produce LXA₄, further worsening the imbalance between proinflammation and anti-inflammation (Feng et al., 2017). ATL attenuates LPS-induced proinflammatory responses and the production of nitric oxide by inhibiting the activation of NF-κB and MAPKs via FPR2/ALX in BV-2 microglial cells (Wang et al., 2011). ATL could also abrogate NADPH oxidase-mediated ROS generation, subsequently inhibiting oxidase activation (Wu et al., 2012c) and M1 activation in microglia (Taetzsch et al., 2015). Recently, studies have demonstrated that LXs regulated microglial activation through the Notch signaling pathway (Wu et al., 2019b; Li et al., 2021), working as a repressor of inflammatory reactions in the brain. In fact, the supposed dichotomy between M1 and M2 phenotypes is oversimplified. Recent transcriptomics and proteomics studies have identified a multitude of activated microglial phenotypes in diverse disease stages (Beaino et al., 2021). To boost the correct microglial phenotype, it is necessary to further study the role and the underlying mechanism of LXs in regulating microglial activation, especially in vivo.

The effects of LXs on macrophages in the resolution of inflammation have been elucidated. LXs could mediate macrophage recruitment, improve the nonphlogistic phagocytosis of apoptotic neutrophils by macrophages (Godson et al., 2000), and increase macrophage survival via inhibition of apoptosis (Prieto et al., 2010) and regulation of autophagy (Prieto et al., 2015). In addition, LXs could also shift the macrophage phenotypic profile to an M2 state (Vasconcelos et al., 2015). Recently, disease-associated microglia (DAM) have attracted the attention of scientists. DAM are phagocytic cells conserved in mice and human and are associated with neurodegenerative diseases, such as AD and amyotrophic lateral sclerosis (Keren-Shaul et al., 2017). They are localized near amyloid plaques (Aβ) and participate in the dismantling and digestion of Aβ. Similar phagocytosis of DAM and macrophages suggests that there may also be a link between LXs and DAM. However, to date, we have not found studies on the roles of SPMs in DAM. The issue may become a hot spot of research 1 day in the future.

In the CNS, as crucial players in maintaining brain homeostasis, astrocytes contribute to the formation of the BBB, secrete neurotrophic factors and modulate synaptic transmission. Although not all astrocytic responses attenuate inflammation, their predominant function is to protect the brain from injury by regulating the neuroinflammatory response (Cekanaviciute and Buckwalter, 2016). Anti-inflammatory and antioxidant effects of LXs have been characterized in astrocytes. LXA₄ could inhibit IL-1β-induced IL-8 and intercellular cell adhesion molecule-1 (ICAM-1) expression in 1321N1 human astrocytoma cells, thus reducing the infiltration of immune cells (Decker et al., 2009). In neonatal rat astrocyte primary cultures suffering oxygen-glucose deprivation/recovery, LXA₄ inhibited LTC4 and LTA4 biosynthesis as well as 5-LOX translocation through an extracellular signal-regulated kinase (ERK) signal transduction pathway (Wu et al., 2012a). In response to LPS-induced neurotoxicity, ATL suppressed the production of nitric oxide and PGE₂ through an NF-κB-dependent mechanism (Yao et al., 2014). In addition, LXA₄ was found to downregulate the expression of aquaporin 4, which may be another anti-inflammatory target of LXA₄ (Wu et al., 2019a). Furthermore, LXA₄ could induce heme oxygenase-1 (HO-1) expression and glutathione (GSH) release as well as Nrf2 expression, of which nuclear translocation was partly ascribed to excess p62 accumulation, hence diminishing oxidative stress (Wu et al., 2015).

In the context of CNS inflammation, there is sophisticated crosstalk between astrocytes and other cells in the CNS (Linnerbauer et al., 2020). Moreover, the roles of astrocytes can be multifaceted. The regulation of astrocytes by LXs remains to be further studied. Whether LXs can regulate the communication between astrocytes and other cells cannot be ignored, either.

In addition to the cells mentioned above, LXs also regulate the activation and migration of leukocytes (Liu et al., 2019), exert anti-inflammatory and antiangiogenic effects on endothelial cells (Baker et al., 2009), and modulate activated endothelial leukocyte interactions (Smith et al., 2015), which are not discussed here.

The exact mechanisms responsible for ischemic stroke are not fully understood. Inflammation following ischemia-reperfusion plays a pivotal role in the pathophysiology of ischemic stroke and related brain injury (Mizuma and Yenari, 2017; Rajkovic et al., 2018). The generation of LXA₄ after ischemic stroke has been detected in both animal models and clinical patients. Marcheselli et al. (2003) determined the LXA₄ production in the hippocampus of mice after 1 h of middle cerebral artery occlusion (MCAO) followed by reperfusion and found a tendency for an increase in plasma LXA₄ levels after injury, which peaked within 8 h and lasted for 24 h. Similarly, plasma LXA₄ levels were measured, and it was determined that they increase in rats after global cerebral ischemia (GCI). Due to the long interval between observations, LXA₄ did not change up to 6 h but tended to increase at 24 and 72 h and remained elevated until 168 h post-GCI (Jung et al., 2020). In the blood of patients after ischemic stroke, there was also a significant increase in LXA₄ on the seventh day after the incident, indicating that LXA₄ is one of the most important derivatives after an early incident of ischemic stroke (Szczuko et al., 2020).

The neuroprotection of LXs has been well established in ischemic stroke. It was first evaluated by Sobrado et al. (2009), who demonstrated that intracerebroventricular administration of LXA₄ (1 nmol) caused a decrease in both infarct volume and neurological deficit scores after MCAO and confirmed that it was partially mediated by PPARγ. Then, You Shang et al. conducted further investigation on the efficacy of LXs using LXA₄ ME in the same model and reconfirmed the neuroprotection of LXs in ischemic stroke (Wu Y. et al. 2010). They found that LXA₄ ME could suppress neutrophil infiltration and lipid peroxidation levels, inhibit the activation of microglia and astrocytes and modulate the ratio of proinflammatory cytokines and anti-inflammatory cytokines, which were associated with the inhibition of the NF-κΒ pathway (Wu et al., 2010; Ye et al., 2010). In a later experiment, they demonstrated that LXA₄ ME could also improve blood-brain barrier (BBB) integrity through the upregulation of metallopeptidase inhibitor-1 and the subsequent downregulation of matrix metallopeptidase (MMP)-9 expression and activity (Wu et al., 2012b). Recently, it was also shown that LXA₄ exerted a neuroprotective effect on ischemic stroke by regulating microglial M1/M2 polarization via the Notch signaling pathway (Li et al., 2021). In accordance with these findings, it has been shown that BML-111, another LXA₄ analog, could also alleviate neuroinflammation and maintain BBB integrity after ischemic stroke by decreasing the levels of MMP-9 and MMP-3 and protecting tight junction proteins in an ALX-dependent manner (Hawkins et al., 2014). In the following experiment, researchers attempted to further confirm the long-term effects of BML-111 on neurological recovery at 4 weeks after ischemic stroke in rats, but frustratingly, they failed (Hawkins et al., 2017). Vital et al. have focused on the ATL effects within the cerebral microvasculature. They found that ATL activated FPR2/3 and inhibited leukocyte-endothelial interactions to initiate endogenous pro-resolution (Smith et al., 2015) and inhibited neutrophil-platelet aggregation to prevent secondary embolism (Vital et al., 2016).

Le Wu et al. explored the anti-inflammatory and antioxidant mechanisms underlying the neuroprotective effects of LXA₄ in ischemic stroke. They demonstrated that LXA₄ could inhibit 5-LOX translocation and leukotriene biosynthesis both in vivo and in vitro, which are partly mediated by FPR2/ALX and through an ERK signal transduction pathway (Wu et al., 2012a). They also confirmed in vivo and in vitro that LXA₄ could induce Nrf2 expression and its nuclear translocation, as well as HO-1 expression and GSH synthesis (Wu et al., 2013; Wu et al., 2015). Of interest, these pathways may be independent of FPR2/ALX and more closely related to p62 accumulation.

Cognitive impairment and depression are the most common complications of stroke, and it seems that LXs are associated with the outcomes. In terms of poststroke cognitive impairment (PSCI), it was reported that, compared with patients without PSCI, the levels of LXA₄ were significantly reduced in PSCI patients, and the LXA₄ levels were positively correlated with the Mini-Mental State Examination scores (Wang et al., 2021). Inspiringly, LXA₄ pretreatment has been verified to improve cognitive function in aged rats after global cerebral ischemia-reperfusion (Wu et al., 2018). Regarding poststroke depression, it was shown that the changes in the Beck Depression Inventory-II scores of patients after stroke were inversely correlated with LXA₄ level, hinting that LXA₄ may also be a protective factor for the prevention of depression after stroke (Kotlega et al., 2020). In addition, it was investigated that the activation of FPR 2/3 could inhibit the action of glucocorticoids on the hypothalamic-pituitary-adrenal axis and maintain hippocampal homeostasis by preventing neuronal damage associated with depression (Peritore et al., 2020). Therefore, it is conceivable that LXs may confer neuroprotection in depression through the activation of FPR 2/3.

For ischemic stroke, diabetes mellitus is one of the major risk factors, and atherogenesis is the most common etiology. Excitingly, LXA₄ has been reported to protect against inflammatory reactions in diabetic cerebral ischemia/reperfusion (I/R) injury, and its mechanism may be related to the inhibition of TNF-α and NF-κB expression (Han et al., 2016). Besides, LXA₄ and ATL could compromise foam cell formation, oxidized low-density lipoprotein-induced inflammation and apoptotic signaling in macrophages during atherogenesis, which could be instructive for ischemic stroke prevention (Petri et al., 2017; Mai et al., 2018).

In conclusion, LXs are a promising therapeutic agent to better resolve the aggressive inflammatory state after ischemic stroke and limit irrecoverable neuronal damage. At present, the observed neuroprotective effects of LXA₄ can last at least 72 h in the model of MCAO/reperfusion when administered immediately after ischemia (Wu et al., 2012a). Although BML-111 failed to show long-term neuroprotective effects, it remains to be explored whether other LX analogs can be protective up to weeks following ischemia and contribute to long-term functional recovery. On the other hand, in terms of LX administration, which dose to use, when to administer it, and how frequently may influence the results, offering new ideas for us to obtain a long-term protection from LXs (Han et al., 2016).

Subarachnoid hemorrhage and intracerebral hemorrhage (ICH) are the two types of hemorrhagic stroke, in which inflammation is a vital pathologic manifestation of early brain injury and a crucial factor related to the outcome (Lucke-Wold et al., 2016; Xue and Yong, 2020). It has been confirmed that LXs can exert protective effects in SAH. The expression of endogenous LXA₄ was decreased and its receptor FPR2/ALX was increased in the hippocampal and cerebral arteries after SAH, indicating a depletion of anti-inflammation (Guo et al., 2016). Exogenously injected LXA₄ (1.0 nmol) at 1.5 h after SAH could significantly alleviate the pathology of SAH, including reducing brain edema, preserving BBB integrity, improving neurological scores, and enhancing spatial learning and memory abilities. In this experiment, the FPR2/p38 MAPK signaling pathway was shown to be involved in the anti-inflammatory pathway elicited by LXA₄ (Guo et al., 2016). In addition, LXA₄ could significantly ameliorate endothelial dysfunction, recover microflow and protect against inflammation by inhibiting neutrophil infiltration. The beneficial effects of LXA₄ on endothelial function might be partly dependent on the inhibition of NF-κB via the FPR2/ERK1/2 pathway (Liu et al., 2019).

The preemptive treatment of unruptured intracranial aneurysms (IAs) is the first goal in the prevention of SAH. Frustratingly, except for open surgery and endovascular intervention, there is no noninvasive medical treatment for IAs. By targeting inflammation, nonsteroid anti-inflammatory drugs (NSAIDs) and statins exert a suppressive effect on IAs (Aoki et al., 2008; Hasan et al., 2011). Recently, eicosapentaenoic acid, the precursor of resolvin E1 targeting GPR120, was also reported to suppress the size of IAs and degenerative changes in the media in rats by suppressing NF-κB activation (Abekura et al., 2020). Considering the strong modulation of inflammation of SPMs, LXs may also have an effect on IAs. LXA₄ may serve as an alternative treatment for SAH and is worthy of further exploration.

For ICH, it has been reported that LXA₄ ME could inhibit neuronal apoptosis, decrease the levels of proinflammatory cytokines and improve neurologic function by inhibiting the NF-kB-dependent MMP-9 pathway in a rat model of ICH (Song et al., 2019). LX treatment may be a potential therapy after brain hemorrhage. In the future, more studies are needed to determine the potential role of LXs in ICH and to clarify the protective mechanism.

Neonatal hypoxia-ischemia (HI) encephalopathy is the most common clinical brain injury in the perinatal period (Hagberg et al., 2015). Recently, the neuroprotective effects of LXA₄ were reported in a rat model of neonatal HI brain injury (Zhu et al., 2020). LXA₄ treatment suppressed acute inflammation and oxidative stress following brain injury in addition to preventing BBB disruption by regulating the IκB/NF-κB signaling pathway, which consequently attenuated HI brain damage. Furthermore, LXA₄ succeeded in exerting long-term neuroprotection, which involved promoting the recovery of neuronal function and tissue structure 7 days post-HI and ameliorating motor and learning functioning 21 days after HI. Moreover, LXA₄ significantly inhibited neuronal apoptosis both in vivo and in vitro experiments. Although there is a lack of sufficient research support, LXA₄ raises new hope for HI, and further studies are required to elucidate the mechanisms underlying protection. Additionally, it is valuable to explore whether combined LXA₄ treatment with hypothermia, the only effective treatment recognized in HI clinical practice, can produce more pronounced improvements in HIE.

In traumatic brain injury (TBI), following mechanical damage from an impact, called “primary injury,” a complex cascade of physiologic reactions will result in a secondary injury, among which primary BBB disruption and inflammatory response are the critical pathological steps (Jassam et al., 2017). AA products involving 5-HETE, 12-HETE and TXB2 were all increased in patients’ CSF 1–4 days following TBI (Shearer and Walker, 2018). In contrast, plasma LXA₄ levels showed a tendency to decrease after TBI from 6 h up to 168 h in a controlled cortical impact rat model of TBI (Jung et al., 2020). These results indicate that proinflammatory activity rather than resolving activity is the dominant theme in TBI, which may lead to detrimental consequences, including increased intracranial pressure, brain edema, and brain herniation.

Neuroinflammation is proposed as an important manipulable aspect of secondary injury in animal and human studies. LXA₄ treatment was shown to effectively reduce BBB permeability, brain edema and lesion volume 24 h post-TBI in mice (Luo et al., 2013). These protective effects of LXA₄ were associated with the inhibition of proinflammatory cytokines (TNF-α, IL-1β and IL-6) and the activation of MAPK pathways (p-ERK and p-JNK but not p-p38). Of interest, LXA₄ enhanced the activation of ALXR in astrocytes instead of microglia at 24 h after injury, but the exact mechanism is still unclear. The limitation of the study was that it only focused on the effects of LXA₄ on the early changes within 24 h after TBI. In fact, the efficacy of TBI therapies is influenced by the type (focal vs. diffuse), stage (acute vs. chronic), severity, and location of the injury. Moreover, TBI can cause lifelong and dynamic influences such as sustained cognitive and psychiatric disorders, sleep-wake disturbances and neurodegeneration (Moretti et al., 2012; Sandsmark et al., 2017; Wilson et al., 2017). Therefore, more studies about the protective effect of LXs on TBI remain to be conducted.

After spinal cord injury (SCI), incomplete or delayed resolution usually occurs and can lead to detrimental effects, including propagated tissue damage and impaired wound healing. First, the clearance of inflammatory cells containing neutrophils, macrophages, microglia and lymphocytes was impaired after SCI. Second, the synthesis of SPMs was delayed after contusion injury. The levels of 12-HETE and 15-HETE, which are pathway markers of the synthesis of LXA₄, did not increase until 14 days after injury (Francos-Quijorna et al., 2017).

Exogenous administration of LXs has shown protective effects against SCI in animal models. LXA₄ suppressed the damage induced by I/R in rabbits through its antiapoptotic and antioxidant activities (Liu et al., 2015). In a model of spinal cord hemisection, LXA₄ inhibited microglial activation, moderated neuroinflammation and attenuated mechanical allodynia (Martini et al., 2016). Moreover, LXA₄ upregulated Akt/Nrf2/HO-1 signaling, contributing to the improvement in functional recovery, attenuation of allodynia and hyperalgesia, reduction of lesion volume and inhibition of apoptotic signaling after SCI (Lu et al., 2018). Recently, BML-111 has also been reported to protect against SCI by suppressing inflammation and oxidative stress (Liu J. et al., 2020). Collectively, LXs may be considered a potential therapeutic agent for SCI and its associated complications.

The AD brain is marked by the accumulation of extracellular senile plaques and intracellular neurofibrillary tangles composed of Aβ and hyperphosphorylated-tau protein (p-tau), respectively. The etiological mechanisms underlying these neuropathological changes remain unclear, but dysregulation of glial cells, especially microglia, and elevated neuroinflammation make great contributions to disease progression (Heneka et al., 2015). The decreased levels of LXA₄ are in line with the fact that the inflammation fails to be resolved in the AD brain. In the brain of 3xTg-AD mice, the levels of LXA₄ were significantly lower than those in the brains of nontransgenic mice. As the best-known risk factor for AD, age reduced LXA₄ levels with a pattern that showed a greater impact in AD mice (Dunn et al., 2015). Similar results were also found in the hippocampus of 5xFAD mice (Kantarci et al., 2018) and neurons from APP/PS1 mice (Lee et al., 2018). The latter study also uncovered that the decrease in 15-R-LXA₄ might be related to the reduction in neural sphingosine kinase 1. Generally, sphingosine kinase 1 can acetylate COX2 to increase SPM secretion, increase microglial phagocytosis and improve AD-like brain pathology, including abnormal inflammation and neuronal dysfunction.

Marianne Schultzberg’s team analyzed postmortem brain tissues and CSF samples from AD patients concerning the production of SPM. In accordance with the findings in mice, the levels of LXA₄ were reduced in both the postmortem CSF and hippocampus of AD patients (Wang et al., 2015). The decline in LXA₄ synthesis was independent of the enzyme 15-LOX-2 since its expression in AD brains was elevated. They also found a positive correlation between the Mini-Mental State Examination scores and the levels of LXA₄, showing the importance of LXA₄ in maintaining normal cognition. Of interest, they verified the AD-related alterations in the entorhinal cortex, but no difference was found with regard to LXA₄, revealing its tissue-specific expression (Dunn et al., 2015). In the study, they also detected the level of FPR2/ALX and found an increase in AD brains, which would make the tissue more responsive to pro-resolving signaling. However, the influence of LXA₄ on the chemotaxis and production of reactive oxygen species in phagocytic cells also occurs via FPR2/ALX (Tiffany et al., 2001), which makes the role of the FPR2/ALX in AD progression more complicated.

In AD, several lines of evidence have shown the neuroprotective effect of LXA₄. It was first demonstrated in the cortex and hippocampus of mice and BV2 microglial cells exposed to Aβ1–42. LXA₄ inhibited the production of IL-1β and TNF-α via the NF-κB signaling pathway both in vivo and in vitro (Wu et al., 2011). LXA₄ also displayed neuroprotection against spatial memory impairment induced by Aβ1–40 in a cannabinoid 1 receptor-dependent manner in mice (Pamplona et al., 2012). Whether PPAR-γ mediates the neuroprotective effects of LXA₄ remains unknown, but the levels of PPAR-γ were markedly higher in AD than in the control compensatory reaction to the decreased levels of LXA₄ (Wang et al., 2015). In addition, LXA₄ alleviated oxidative stress-driven neuroinflammation in rats by targeting redox-sensitive proteins, including heat shock protein 72 and HO-1 (Trovato et al., 2016).

ATL also exerted neuroprotective effects on AD-like pathology in mice. ATL switched microglia from the classic phenotype to the alternative phenotype, thus improving the phagocytic function of microglia. Altered microglia promoted clearance of Aβ deposits and ultimately reduced synaptotoxicity and restored cognitive function in Tg2576 mice. According to the study, ATL can activate FPR2/ALX and reduce NF-κB activation in astrocytes, sequentially potentiating the action of alternative microglia (Medeiros et al., 2013). However, there was no significant effect on Aβ₄₂ phagocytosis in CHME-3 microglia using LXA₄ (Zhu et al., 2016). Apart from reducing Aβ levels, ATL could also decrease the levels of p-tau and enhance the cognitive performance of 3xTg-AD mice (Dunn et al., 2015). The decrease in p-tau was in part due to the inhibition of tau kinases GSK-3β and p38 MAPK. Additionally, microglial and astrocyte reactivity was inhibited by ATL treatment.

Combining LXA₄ with other SPMs is a promising strategy to reverse the neuroinflammatory process associated with AD pathology since different SPMs have distinct selective functions and can regulate the process at multiple levels. Strong support is provided by the fact that combined treatment with LXA₄ and resolvin E1 resolved AD-associated neuroinflammation and restored cognitive deficits more effectively than LXA₄ treatment alone in 5xFAD mice (Kantarci et al., 2018). There have been several investigations on AD patients treated with dietary supplementation with SPM precursors (Kotani et al., 2006; Janssen and Kiliaan, 2014). For instance, it was shown that dietary supplementation with 240 mg/d AA and docosahexaenoic acid for 90 days improved the immediate memory and attention scores of patients with mild cognitive dysfunction. However, clinical trials in which human AD patients are directly treated with SPMs to correct the deficiency have not yet been performed.

Previous studies on AD tended to focus on “anti-inflammation” rather than “pro-resolution.” Although epidemiological studies have suggested that patients with protracted NSAID use have a lower prevalence of dementia (McGeer et al., 1996), clinical trials with NSAIDs have thus far yielded disappointing results (Cunningham and Skelly, 2012; Cudaback et al., 2014; Heneka et al., 2015). In contrast to “anti-inflammatory” treatments, SPMs do not block the enzymatic activity to regulate the inflammatory process. Instead, they interact with specific receptors to promote the beneficial and restorative aspects of inflammation. The LX dysregulation in neurodegeneration is attracting more and more attentions (Kim et al., 2020). We think that the intervention of LXs based on inflammatory resolution may give AD a chance to return to normal.

Excessive neuroinflammation is a crucial pathological hallmark of multiple sclerosis (MS). Gijs Kooij and his colleagues revealed that the majority of SPMs, including LXA₄ and LXB₄, were significantly reduced in MS and correlated with disease progression through targeted lipid metabololipidomics in the plasma of MS patients (Kooij et al., 2020). They also found that the expression of SPM-related biosynthetic enzymes and receptors in blood-derived leukocytes of MS patients was impaired. In vitro, LXA₄ and LXB₄ were found to reduce MS-derived monocyte activation and cytokine production, improve BBB function and inhibit monocyte transmigration in MS patients (Kooij et al., 2020). In vivo, LXA₄ administration ameliorated clinical signs of experimental autoimmune encephalomyelitis (EAE) in mice by normalizing the EAE-induced spinal cord lipidome and modulating Th1 and Th17 responses (Derada Troletti et al., 2021), which further highlighted the potential clinical application of LXs for MS.

Chronic cerebral hypoperfusion (CCH) is a chronic and silent disease characterized by sustained defects in brain perfusion. In recent years, as increasing evidence suggests the critical roles of CCH in the initiation and progression of vascular dementia and AD (Duncombe et al., 2017), CCH has garnered increasing attention from scientists and clinicians. Interestingly, LXs have been shown to exert beneficial effects against cognitive and neuropathological changes in CCH. LXA₄ ME could exert neuroprotection in CCH by regulating endoplasmic reticulum stress and macroautophagy (Jia et al., 2015). LXA₄ ME could also attenuate oxidative injury and reduce neuronal apoptosis related to CCH through activation of the ERK/Nrf2 signaling pathway in the rat hippocampus (Jin et al., 2014). Therefore, it is conceivable that the application of LXs in the future might provide beneficial effects for patients with CCH and ameliorate the related decline in cognition.

Neuropathic pain is attributed to lesions affecting the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified (Costigan et al., 2009). There is abundant evidence for the involvement of inflammatory mediators in neuropathic pain. The development of allodynia and hyperalgesia is correlated with the release of TNF-α, IL-1β and IL-6, whereas antagonism or their knockout leads to the opposite effect. The mechanism of their action is not well established; nevertheless, they can directly excite nociceptors or indirectly maintain sensory abnormalities by modulating synaptic transmission and pain hypersensitivity (Marchand et al., 2005). It has been determined that the spinal cord, especially the astrocytes within it, can express FPR2/ALX in vivo and in culture (Svensson et al., 2007; Abdelmoaty et al., 2013; Wang et al., 2014). LX treatment has been reported to alleviate neuropathic pain under various pathological conditions, including opioid-induced hyperalgesia, peripheral nerve injury and spinal cord injury. The effect of LX on analgesics is primarily associated with its anti-inflammatory and pro-resolution properties.

LXA₄ ME attenuated morphine antinociceptive tolerance and withdrawal-induced hyperalgesia. This prevention was correlated with the inactivation of NF-κB, inhibition of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), and upregulation of anti-inflammatory cytokines (IL-10 and transforming growth factor-β1). According to the authors’ perspective, the actions of LXA₄ ME were achieved by interacting with the Toll-like receptor 4 cascade, which has been verified as a contributor to painful neuropathy (Tanga et al., 2005), rather than opioid receptors (Jin et al., 2012). However, another study revealed the involvement of the μ-receptor/phosphoinositide-3-kinase (PI3K)-Akt signaling/NAcht leucine-rich-repeat protein 1 (NALP1) inflammasome cascade in this process and found that ATL could block this signaling cascade (Tian et al., 2015).

In chronic constriction injury (CCI)-induced neuropathic pain, ALT potently suppresses thermal and mechanical hyperalgesia and significantly inhibits NALP1 inflammasome activation, caspase-1 cleavage, and IL-1β maturation (Li et al., 2013). Further investigation indicated that the analgesic effect of ATL was mediated by inhibiting spinal JAK2/STAT3 signaling through FPR2/ALX and hence suppressing spinal neuroinflammation in CCI rats (Wang et al., 2014). In line with this discovery, LXA₄ exerted similar antinociceptive effects in a model of chronic dorsal root ganglia compression in rats (Sun et al., 2012). Moreover, LXA₄ potently alleviated radicular pain in a rat model of noncompressive lumbar disc herniation by attenuating the activation of NF-κB/p65, p-ERK and p-JNK, but not p-p38, in the dorsal root ganglion (Miao et al., 2015). Another study showed that LXA₄ inhibited NLRP3 activation and autophagy in the dorsal root ganglion by regulating the JNK1/beclin-1/PI3KC3 axis, thus participating in its analgesic effects (Jin et al., 2020).

LXA₄ also exhibited analgesic activity against SCI-induced neuropathic pain, as evidenced by an increase in the mechanical paw withdrawal threshold in a model of SCI in both mice and rats (Martini et al., 2016; Lu et al., 2018). The antinociceptive effects of LXA₄ were mediated by FPR2/ALX and might be partly attributable to the decline in TNF-α from microglia (Martini et al., 2016). In addition, LXs could prevent the phosphorylation of ERK and JNK in astrocytes by activating FPR2/ALX (Svensson et al., 2007; Hu et al., 2012).

Recently, roles of SPMs in neuropathic pain were elucidated, suggesting that SPM can be promising targets to counteract neuropathic pain (Leuti et al., 2021). SPM represent the endogenous inhibitors of transient receptor potential cation channel subfamily V member 1 (TRPV1), which has been confirmed with Resolvin E1 and protectin 1. To date, it remains unknown whether LXs has an effect on TRPV1. Due to the intricated relationship between inflammation and pain, it is necessary to better understand the cellular and molecular pathways associated to the analgesia of LXs.

In recent years, the protection of LXs has been underscored in a variety of central nervous system infections. First, LXs generated in a 5-LO-dependent manner have been demonstrated to control proinflammatory and type 1 T helper cells’ immune responses against M. tuberculosis infection (Bafica et al., 2005). Aspirin can improve outcomes from tuberculosis meningitis, which is speculated to be related to the production of ATL (Tobin et al., 2012). However, in a randomized placebo-controlled trial of adjunctive aspirin treatment in adults with tuberculosis meningitis, ATL concentrations were not changed by aspirin treatment, but it confirmed that SPM concentrations, including ATL in CSF, were associated with disease severity and outcome (Colas et al., 2019). In Plasmodium berghei-infected mice, LXA₄ not only prolonged survival by inhibiting IL-12 production and CD8(+) IFN-γ(+) T cells (Shryock et al., 2013) but also ameliorated endothelial dysfunction by modulating ICAM-1 and HO-1 expression in brain tissue (Souza et al., 2015). Moreover, by generating LXA₄ (Aliberti et al., 2002), wild-type mice avoid succumbing to encephalitis after Toxoplasma gondii infection. Notably, it has been proven that FPR2/ALX plays a pivotal role in glial cell activation in bacterial infection of the CNS (Braun et al., 2011), hinting that LXs may also have an effect on bacterial meningitis.

There is also evidence of the neuroprotective effect of LXs on epilepsy and retinal diseases. The LXA₄ level and FPR2/ALX expression in the cortex and hippocampi of rats were greater in pentylenetetrazole-kindled rats than in the saline group. Aspirin can downregulate the levels of FPR2/ALX and LXA₄, elevating the seizure threshold and helping achieve seizure control (Abd-Elghafour et al., 2017). Astrocyte-derived LXA₄ and LXB₄ have been reported to have a protective effect on the retina against acute kainic acid-induced injury and chronic glaucoma in vivo and to simultaneously dampen paraquat-induced oxidative stress in vitro (Livne-Bar et al., 2017). Recently, it was further characterized that intravitreal injection of LXA₄ delayed the progression of retinal degeneration in mice through the modulation of microglial activities to suppress retinal inflammation and rescue photoreceptors (Lu et al., 2019).