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Specialized Pro-Resolving Mediators in Neuroinflammation
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27154836

Specialized pro-resolving mediators (SPMs) are lipid mediators derived from poly-unsaturated fatty acids (PUFAs) which have been demonstrated to play an important role in the inflammation environment, preventing an overreaction of the organism and promoting the resolution of inflammation.

specialized pro-resolving mediators resolvins maresins annexins lipoxins protectins neuroinflammation neurodegeneration cerebrovascular disorders multiple sclerosis

1. Specialized Pro-Resolving Mediators: Metabolism, Receptors, Pathways

1.1. Overview on Specialized Pro-Resolving Mediators

Inflammation is a cascade event preserved along the evolution from the first multicellular precursor organisms to humans. Its main role is to defend tissues from an insulting agent, such as microbes or direct damage, enabling in most cases a natural return to homeostasis. If inflammation is not someway stopped, it can lead to serious consequences, such as uncontrolled edema [1].
For many years, it was assumed that inflammation was a self-limiting process [1]. However, recent discoveries have shown the presence of an active de-escalation process, promoted by a class of molecules, namely specialized pro-resolving mediators (SPMs). From the beginning of the inflammation process, SPMs reach the site of edema, either transported by blood flow or produced within the inflammatory tissue [1]. Since chronic and/or uncontrolled inflammation plays a key role in a variety of diseases (such as cardiovascular diseases, metabolic syndrome, and neurological diseases), SPMs have a potential therapeutic role. In particular, SPMs are lipid mediators (LMs) derived from PUFAs (poly-unsaturated fatty acids), such as AA (Arachidonic Acid), EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid) and n-3 DPA (n-3 docosapentaenoic acid). The properties of ω-3 fish oil fatty acids in human disease and physiology may in part be explained by the formation of autacoids derived from PUFAs [1]. SPMs include lipoxins, resolvins, protectins and maresins, as well as newly identified cysteinyl-conjugated SPMs (cys-SPMs) and n-3 DPA-derived SPMs [2]. In the following paragraphs, each group of SPMs will be analyzed.

1.1.1. Lipoxins

Lipoxins (LX) LXA4 and LXB4 [1][3] were the first discovered SPMs. Lipoxins derive from eicosanoids thanks to a mechanism of lipo-oxygenation. Eicosanoids in turn derive from AA, an ω-6 fatty acid implied in inflammation. AA is converted into LXA4 and LXB4 via 5- lipoxygenase and 15- lipoxygenase. Lipoxins are produced by leukocytes in transcellular biosynthesis steps during interactions between leukocytes and mucosal cells or platelets [1]. Initially, Lipoxins were believed to be agents of anti-inflammation, and their pro-resolution role has only recently been discovered. Aspirin can trigger their biosynthesis thanks to its capacity to promote the formation of LMs via lipo-oxygenation [4].

1.1.2. Resolvins

Resolvins are generated in inflammatory exudates during the phase of resolution. They derive from ω-3 fatty acids EPA and DHA, forming E series (RvE) and D series (RvD) resolvins, respectively. Their synthesis is also promoted by aspirin (likewise Lipoxins) [1]. Resolvins act in several ways in order to interrupt the inflammation cascade. In particular, they [1]:
  • inhibit the production of pro-inflammatory mediators, such as chemokines and cytokines
  • enhance scavenging of pro-inflammatory chemokines
  • promote the recruitment of monocytes and phagocytes’ clearance via the lymphatic system
  • limit PMN (polymorphonuclear cells) migration and infiltration
  • Focusing on the subclass of Resolvins, it can be found [2]:
  • E-series Resolvins: RvE1, RvE2, RvE3 and the recent RvE4;
  • D-series Resolvins: RvD1, 17R-ResolvinD1, RvD2, RvD3 and 17R-Resolvin D3, RvD4, RvD5.

1.1.3. Protectins

Protectins consist of Protectin D1/Neuroprotectin D1 (PD1/NPD1). They are biosynthesized from DHA via the 15-LOX mechanism. It can be found in human cell types, murine exudates and brain tissue; in this last case, it is called “NeuroprotectinD1” (NPD1), whereas PD1 operates in peripheral tissue. PD1/NPD1 has neuroprotective properties in the brain, retina and Central Nervous System (CNS). Its aspirin-triggered epimer, 17R-NPD1, has the same actions as NPD1 in controlling PMN, enhancing macrophage functions and attenuating experimental stroke [2].

1.1.4. Maresins

Maresins were first identified in human macrophages, in a pathway initiated by 12-LOX. Their name derives from an acronym: Macrophage Mediators in Resolving Inflammation. Maresin1 (MaR1) is able to promote the regeneration of tissues in an experimental model of simple organisms (planaria) with a strong capability of regeneration. In human cells, it is produced by platelets and PMN interactions. MaR1 promotes tissue regeneration and repair and has a neuroprotective role [2].

1.1.5. Recently Discovered SPMs

Recently discovered peptide-lipid conjugated SPMs include cysteinyl-SPMs (cys-SPMs). They consist of three series of SPMs, each one with three bioactive members: maresin conjugates in tissue regeneration (MCTR), protectin conjugates in tissue regeneration (PCTR) and resolving conjugates in tissue regeneration (RCTR). They show pro-repair and pro-regenerative actions [2]. For the sake of completeness, it is important to mention n3-DPA-derived SMPs: RvDn-3 DPA, MaRn-3 DPA and PDn-3 DPA, 13-series resolvins (RvTs). They share the potent actions of DPA and EHA-derived SPMs in the resolution of systemic inflammation and neuro-inflammation. RvTs’ biosynthesis is promoted by atorvastatin via S-nitrosylation of cyclooxygenase-2 (COX-2) [2].

1.2. Receptors and Pathways

It is important to emphasize that these endogenous mediators of resolution do not act thanks to an “inhibition” of inflammation pathways: instead, they actively promote specific pathways in order to obtain a return to homeostasis. There are specific G-protein-coupled seven-transmembrane receptors (GPCR) activated by SPMs [1]. Every single class of SPM demonstrates stereoselective activation of its own GPCR. SPMs show affinities for ligand-receptors in the nano-picomolar range, thus demonstrating a potent action in vitro and in vivo [2].
Resolvin E1 (RvE1) acts via ChemR23 (GPCR for RvE1). It is also a partial agonist on the LTB4 (leukotriene B4) receptor (BLT1), activated by LTB4 as well. Nevertheless, RvE1 has a different mechanism of action, which is a time and dose-dependent phosphorylation of Akt and p70S6K (ribosomal protein S6 kinase) via ChemR23 [1].
Resolvin D1 (RvD1) binds two separate GPCR on human leukocytes: ALX/FPR2 (LXA4 receptor) and GPR32 (GPCR for RvD1) [1]. ALX/FPR2 receptors can also be activated by Annexin-1 and Chemerin [5]. Deficits in ALX/FPR2 in experimental models (mice) amplify cardiomyopathy, age-related obesity, and leukocyte-directed endothelial dysfunction [6].
MaR1 can activate two classes of receptors:
  • leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), a phagocyte’s receptor
  • retinoic acid-related orphan receptor α (ROR-α), a liver macrophages’ nuclear receptor
Stimulating the LGR6 receptor, MaR1 can promote phagocytosis, efferocytosis, and the phosphorylation of select proteins [7]. NPD1/PD1’s receptor, GPR37, increases intracellular Ca2+ in macrophages and promotes phagocytosis [8]. RvD5n-3 DPA binds an orphan receptor, GPR101, with high stereospecificity [2]; in experimental KO models of GPR101, there is a lack of protective action of RvD5n-3 in inflammatory arthritis [9].
These receptors demonstrate overlapping actions (for example, ALX, GPR18, LGR6 and GPR101 can promote calcium mobilization via cAMP signal) and distinct actions too; thus, they could act in tandem to promote defense from injury, inflammation, and infection [2].

1.3. Mechanism of Action

The first signs of inflammation response are vasodilation and changes in vessel permeability. These factors not only permit the recruitment of cells implied in the inflammatory response but also give substrates for the biosynthesis of important molecules, such as SPMs [1]. Apparently, ω-3 PUFAs, AA, EPA and DHA can be found within inflammatory exudates during very early phases, as demonstrated in various works [10][11]. Therefore, the inflammation response is counterbalanced early by pro-resolution mediators. This avoids an excess of an inflammatory response that can be disruptive for the organism and for the tissue itself [1].

2. Specialized Pro-Resolving Mediators and Neuroinflammation

2.1. Neuroinflammation and Its Resolution

While inflammation is usually a self-limiting physiological process, when persistent or dysregulated it can become harmful to human tissues; if this happens within the CNS it is referred to as neuroinflammation and many studies proved that chronic neuroinflammation could ultimately lead to neurodegeneration [12][13][14]. In this picture, an emerging concept is the resolution of neuroinflammation which contributes to brain homeostasis; a great deal of attention has been paid to the topic in the last few years. The main actors of this specular process are the so-called SPMs, whose characteristics have been explained in the previous chapter. In the last decade, several research groups started to investigate the role of SPMs in the nervous tissue as regulators of the inflammation process that may contribute to the crosstalk between glial cells and neurons in several neurological pathologies [15].

2.2. The Role of Glial Cells in Neuroinflammation and the Contribution of SPMs

Nervous tissue is composed of about 100 billion neurons and 80 to 100 billion glial cells, namely ectoderm-derived astrocytes and oligodendrocytes, and mesoderm-derived microglial cells. Astrocytes play a key role in the metabolism and metabolic support of nervous parenchyma and specifically neurons, i.e., lactate shuttle, the glutamate–glutamine cycle, and ketone bodies supply. Neuroinflammation has lately been interpreted as a condition of metabolic imbalance and energetic depletion, both in the acute and chronic settings. It hence derives that glial cells play a crucial role in the control of neuroinflammation, by regulating nervous tissue metabolism.
As demonstrated, brain tissue contains high levels of PUFAs, mainly DHA and AA, which are the principal precursors of SPMs. The main PUFA source is unesterified plasma fatty acid pool rather than endogenous synthesis; such a source is severely impacted by dietary supply according to studies conducted on rodents [16][17]. Interestingly, the hippocampus and prefrontal cortex contain the highest DHA content while the hypothalamus has the lowest [15]. As for their proportion of representation in the human brain, astrocytes contain 10–12% of DHA, oligodendrocytes 5%, and microglial cells up to 2% [18]. Astrocytes, the most abundant glial cells present in the nervous tissue, take part in many vital processes, such as the migration of developing axons and certain neuroblasts, the regulation of blood flow, electrolyte homeostasis, blood–brain barrier (BBB), and synapse function. Moreover, they seem to be the main glial cells involved in neuroinflammation, although they show significant diversity in this process. For instance, they express high levels of the ALX/FPR2 receptor, which has a central role in the regulation of astrogliosis, an active inflammatory path that leads to neural protection, repair and ultimately to glial scarring [15]. LXA4 and RvD1, the two SPMs that bind this receptor, promote the inhibition of astrocytes’ pro-inflammatory activities [19]. Moreover, it has been observed that peripheral RvD1 administration in brain injury models improved its functional recovery through an ALX/FPR2-regulated pathway probably induced by astrocytes [15]. Another important receptor expressed by astrocytes and playing an important role in neuroprotection is ChemR23/ERV1, expressed in the human hippocampus, which binds RvE1: animal studies demonstrated that peripheral administration of RvE1 in Alzheimer’s disease (AD), in combination with LXA4, reduced astrocyte activation [20]. Other receptors involved in the neuroprotection and resolution of inflammation are GPR37, GPR18 and LgR6, whose expression in astrocytes is challenged, and further studies both in vivo and in vitro are needed on this subset. Besides their main function of myelin synthesis, oligodendrocytes, the second most represented cell population in the CNS, may play a role in the resolution of neuroinflammation thanks to the latest evidence on their active production of immune-regulatory factors or their receptors [21]. Comparing oligodendrocytes with astrocytes, ALX/FPR2 is not expressed by these cells; the only SPMs receptor identified seems to be GPR37 [22]. On the other hand, microglia, the immune cells of the CNS, thanks to their very physiological role, seem to express all the known SPM receptors and are susceptible to the effects of different SPMs categories (lipoxins, RvE, RvD, protectins and maresins) [15][23]. Nonetheless, the cellular origin of SPMs in these cells, as in astrocytes and oligodendrocytes, has not yet been demonstrated and only a few in vitro studies have tried to investigate it [16].

3. Specialized Pro-Resolving Mediators and Potential Applications in Neuroinflammatory Conditions

3.1. Specialized Pro-Resolving Mediators in Ischemic Stroke and Cerebrovascular Events

The concept of ischemic stroke has been expanded to include not only what happens inside the vessel, but also in the surrounding environment, the so-called “neurovascular unit”, which includes the interaction between glia, neurons, vascular cells, and matrix components; after the acute event, secondary neuroinflammation takes place, bringing about detrimental effects producing further injury and neuronal death, and promotion of recovery [24]. Several studies have investigated the possible role of pro-resolving mediators in improving post-stroke prognosis; however, they have mostly been conducted on rodents, and applications in humans remain speculative and in need of further research. Table 1 provides a summary of in vivo studies on SPMs in ischemic stroke and cerebrovascular events.
Table 1. Summary of in vivo studies on SPMs in ischemic stroke and cerebrovascular events.
Table
Reference Type of Study Animal Model Pro-Resolving Mediator Delivery (Or Measurement If the Study Was Non-Interventional) Outcome
Zuo et al., 2018 [25] Animal study MCAO mouse model RvD2 intraperitoneal ↓ infarction, inflammation, edema, and neurological dysfunction; compared with ω-3 fatty acid oral supplements, better rescue effect on cerebral infarction
Dong et al., 2019 [26] Animal study MCAO mouse model RvD2 Intravenous infusion of RvD2-loaded nanovesicles ↓ inflammation;
↑ neurological function
Fredman et al., 2016 [27] Animal study fat-fed Ldlr-/- mice RvD1 Immunoprecipitation injection ↓ atherosclerosis
Kotlęga et al., 2021 [28] Human study - RvD1 blood levels of endogenous pro-resolving mediators Post-stroke blood levels of RvD1 correlated with a better cognitive performance
Xian et al., 2016 [29] Animal study MCAO mouse model MaR1 Intracerebroventricular ↓infarct volume and neurological defects by inhibiting NF-kB p65 function
Xian et al., 2019 [30] Animal study MCAO mouse model MaR1 Intracerebroventricular ↓ inflammation and mitochondrial damage via activation of SIRT1 signaling
Vital et al., 2020 [31] Animal study Lipopolysaccharide and sickle transgenic mice models of thrombo-inflammation AnxA1 mimetic peptide Ac2-26 Intravenous ↓ thrombo-inflammation via Fpr2/ALX receptor and ↓ platelet aggregation
Gavins et al., 2007 [32] Animal study MCAO in wild-type or AnxA1−/− mice AnxA1 mimetic peptide Ac2-26 Intravenous ↓ inflammation via receptors of the FPR family
Xu et al., 2021 [33] Animal study MCAO mouse model AnxA1 mimetic peptide Ac2-26 Intravenous ↓ inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway
Ding et al., 2020 [34] Animal study Collagenase-induced ICH mouse model Recombinant human AnXA1 Intracerebroventricular ↓ inflammation via the FPR2/p38/COX-2 pathway
Senchenkova et al., 2019 [35] Animal study MCAO in wild-type or AnxA1−/− mice Whole protein AnXA1 Intravenous ↓ platelet aggregation by affecting integrin (αIIbβ3) activation
Li et al., 2021 [36] Animal study MCAO mouse model LXA4 Intracerebroventricular ↓ proinflammatory cytokines and regulate microglial M1/M2 polarization via the Notch signaling pathway
Wu et al., 2013 [37] Animal study MCAO mouse model LXA4 Intracerebroventricular ↓infarct volume and ↑ neurological function through Nrf2 upregulation
Hawkins et al., 2014 [38] Animal study MCAO mouse model LXA4 analog BML-111 Intravenous ↓ infarct size, edema, BBB disruption, and hemorrhagic transformation
Hawkins et al., 2017 [39] Animal study MCAO mouse model LXA4 analog BML-111 Intravenous ↓ infarct volume; and
↑ neurological function at 1 week.
No reduction of infarct size or improvement of behavioral deficits 4 weeks after ischemic stroke
Wu et al., 2010 [40] Animal study MCAO mouse model LXA4 ME Intracerebroventricular ↓ proinflammatory cytokines, neurological dysfunctions, infarction volume, and neuronal apoptosis
Ye et al., 2010 [41] Animal study MCAO mouse model LXA4 ME Intracerebroventricular ↓ proinflammatory cytokines, neurological dysfunctions, infarction volume, and neuronal apoptosis
Wu et al., 2012 [42] Animal study MCAO mouse model LXA4 ME Intracerebroventricular ↓ BBB dysfunction and MMP-9 expression;
↑ TIMP-1 expression
Jin et al., 2014 [43] Animal study BCCAO LXA4 ME Intracerebroventricular Amelioration of cognitive impairment via ↓oxidative injury and ↓neuronal apoptosis in the hippocampus with the activation of the ERK/Nrf2 signaling pathway
Wang et al., 2021 [44] Human study - LXA4, RvD1, RvD2, RvE1, MaR1 blood levels of endogenous pro-resolving mediators ↓ LXA4 in patients with post-stroke cognitive impairment
Guo et al., 2016 [45] Animal study endovascular perforation model of SAH Exogenous LXA4 Intracerebroventricular ↓ neuroinflammation by activating FPR2 and inhibiting p38
Liu et al., 2019 [46] Animal study endovascular perforation model of SAH Recombinant LXA4 Intracerebroventricular ↓ endothelial dysfunction and neutrophil infiltration, possibly involving the LXA4/FPR2/ERK1/2 pathway
Yao et al., 2013 [47] Animal study MCAO mouse model NPD1 Intracerebroventricular ↓ infarct volume and ↑ neurological scores through inhibition of calpain-mediated TRPC6 proteolysis and activation of CREB via the Ras/MEK/ERK pathway
Eady et al., 2012 [48] Animal study MCAO mouse model NPD1 Intravenous ↓ infarct size in aged rats via activation of Akt and p70S6K pathways
Belayev et al., 2017 [49] Animal study MCAO mouse model DHA (NPD1 precursor) Intravenous ↓ oxidative stress by upregulating ring finger protein 146 (Iduna) in neurons and astrocyte
Zirpoli et al., 2021 [50] Animal study Unilateral cerebral hypoxia-ischemia injury mouse model NPD1 Intraperitoneal ↓ ischemic core expansion, preserved mitochondrial structure and ↓ BAX translocation and activation
Belayev et al., 2018 [51] Animal study MCAO mouse model NPD1 Intracerebroventricular ↑ neurogenesis and angiogenesis, BBB integrity, and long-term neurobehavioral recovery
Bazan et al., 2012 [52] Animal study MCAO mouse model AT-NPD1 Intravenous ↓ infarct volume and brain edema; ↑ neurobehavioral recovery
AnXA1: Annexin A1; AT-NPD1: aspirin-triggered NPD1; BBB: Blood–Brain Barrier; BCCAO: bilateral common carotid artery occlusion; DHA: docosahexaenoic acid; FPR: formyl-peptide receptor; LXA4: Lipoxin A4; LXA4 ME: Lipoxin A4 Methyl Ester; MaR1: Maresin1; MCAO: middle cerebral artery occlusion; NPD1: Neuroprotectin D1; RvD1: Resolvin D1; RvD2: Resolvin D2; RvE1: Resolvin E1; SAH: Sub Arachnoid Hemorrhage.

3.2. Specialized Pro-Resolving Mediators in Neurological Immune-Mediated Disorders

Multiple sclerosis (MS) is a neuroinflammatory disease in which unresolved and uncontrolled inflammation leads to a pathological disease state, thus representing a classical model of chronic inflammation; in this context, SPMs could be instrumental in resolving the pathologic inflammation. However, there are minimal data available on the functional status of SPMs in MS; it seems that SPMs have neuroprotective action in MS by exerting pro-resolving effects in the pre-clinical model; however, little is known about the direct effect of SPMs on oligodendrocytic or neuronal cells [53]. Table 2 provides a summary of in vivo studies on SPMs in neurological immune-mediated disorders.

Table 2. Summary of in vivo studies on SPMs in neurological immune-mediated disorders.

Table

Reference.

Type of study

Model

Pro-resolving mediator

Delivery (or measurement if the study was non-interventional)

Outcome

Paschalidis N et al., 2009[54]

Animal study

MOG34-55 -induced EAE in AnxA1 null mice compared to MOG34-55 -induced EAE in control mice

Absence of AnxA1 expression

Measurement of disease activity in spinal cord; lymph-node cells (respectively, by isolation of T-cells and/or fixation with haematoxylin and eosin; and by test ELISA for Th1/Th17 cytokine profile)

↓ signs of the disease in AnxA1 null mice compared to wild type mice

↓ infiltration of T cells in the spinal cord of AnxA1 null mice compared to wild type

Huitinga I et al., 1998 [55]

Animal study

EAE rats (MS mouse model)

AnxA1

Intracerebroventricular administration

↓ neurological severity

 

Poisson LM, 2015 [56]

Animal study

EAE rats (MS mouse model)

RvD1

Oral administration

Attenuation of disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells

Derada Troletti C et al., 2021 [57]

Animal study

EAE rats (MS mouse model)

LXA4

Intraperitoneal injection

Improvement of EAE clinical symptoms and inhibit CD4+ and CD8+ T cell infiltration into the CNS

Derada Troletti C et al., 2021 [57]

In vivo and in vitro study

Human T cells from healthy donors and patients with relapsing-remitting MS

 

LXA4

Measurement of T-cell functions

↓ encephalitogenic Th1 and Th17 effector functions

Sánchez-Fernández A et al., 2022 [58]

Animal study

EAE rats (MS mouse model)

MaR1

Intraperitoneal injection

Suppression of various pro-inflammatory cytokines,

↓ number of Th1 cells

↑ of Tregs

polarization of macrophages towards an anti-inflammatory phenotype

Prüss H et al., 2013 [59]

Human study

MS patients

RvD1

NDP1

CSF levels

↑ of RvD1

Only detection of NDP1

Kooij G et al., 2020 [60]

 

Human study

NMOSD patients

RvD1

LTB4

 

CSF levels

RvD1 ↓

LTB4 ↑

Luo B et al., 2016 [61]

Animal study

EAN (experimental autoimmune neuritis) model

RvD1

Intraperitoneal injection

Macrophage phagocytosis of apoptotic T cells in PNS, ↑ TGFβ by macrophages, ↑ local Treg cell counts, and promotion of inflammation resolution and disease recovery

* AnXA1: Annexin A1; AT-NPD1: aspirin-triggered NPD1; BCCAO: bilateral common carotid artery occlusion; DHA: docosahexaenoic acid; EAE: Experimental Autoimmune Encephalitis; EAN: Experimental Autoimmune Neuritis; FPR: formyl-peptide receptor; LXA4: Lipoxin A4; LXA4 ME: Lipoxin A4 Methyl Ester; LTB4: Leukotriene B4; MaR1: Maresin1; NPD1: Neuroprotectin D1; PNS: peripheral nervous system; RvD1: Resolvin D1.

3.3. Specialized Pro-Resolving Mediators in Neurodegenerative Diseases

AD is the most common type of dementia; a growing body of evidence suggests that inflammation is involved in its pathogenesis. Epidemiological studies suggest that the use of anti-inflammatory drugs is associated with a lower incidence of AD; however, clinical trials with anti-inflammatory drugs have not been successful [62]. Given these premises, the possibility of promoting resolution rather than inhibiting inflammation looks appealing.
The potential benefit of working on inflammation resolution is supported by several observations. First of all, a shift in the LM profile in the CSF from pro-resolving to pro-inflammatory occurs as AD progresses: in a recent study, liquid chromatography–tandem mass spectrometry was used to analyze pro-resolving and pro-inflammatory LMs in the CSF of patients with cognitive impairment ranging from subjective impairment to a diagnosis of AD; LMs profile correlated to cognition, CSF tau, and β-amyloid. RvD4, RvD1, NPD1, MaR1, and RvE4 were lower in AD and/or mild cognitive impairment (MCI) compared to subjective cognitive impairment (SCI); on the other hand, pro-inflammatory mediators were higher in AD and MCI [63]. Similarly, it was found that the levels of the MaR1, NPD1 and RvD5, were lower in the entorhinal cortex of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD [64]. In addition, RvD4 showed a negative correlation to AD tangle biomarkers and positive correlations to cognitive test scores [63]. Similar findings have been reported in mice, where SPMs in the brain cortex were substantially lower in mice with an APOE4 genotype [65]. The finding that SPMs receptors are increased in the AD brain in post-mortem studies and correlate to Braak stages, suggests a prominent role of resolution pathways; the increase in these receptors may either represent a primary factor in the pathogenesis of the disease or a consequence of failed resolution [66]. The same study group investigated age-related changes in the LM profile in the APP knock-in (APP KI) mouse model of AD, concluding that the brain lipidome appeared to be modified preferentially during aging as compared to amyloid pathology, as the oldest age group was the one with the greatest increase in LMs, despite an early onset of Aβ pathology [67]. In this case, the SPMs biosynthetic enzymes were found to be increased, while their receptor expression decreased in the aged App KI mice, in disagreement with their previous work [66] on AD patients. The discrepancy may be explained by the fact that the stage of AD pathology in 18-month-old App KI mice is likely less advanced compared to that seen in human post-mortem brains [67]. Several in vivo mouse studies support the potential benefit deriving from SPM use in AD. Table 3 provides a summary of in vivo studies on SPMs in neurodegenerative diseases. 

Table 3. Summary of in vivo studies on SPMs in neurodegenerative diseases.

Table

Reference

Type of study

model

Pro-resolving mediator

Delivery (or measurement if the study was non-interventional)

Outcome

Do K V et al., 2022 [68]

Human, non-interventional

Patients with AD, MCI, SCI

RvD4

CSF levels of RvD4

Negative correlation to AD tangle biomarkers, and positive correlations to cognitive test scores

Zhu M. et al., 2016 [69]

Human study

Patients with AD

MaR1, NPD1, RvD5

Postmortem tissue samples from the entorhinal cortex

↓ concentration of pro-resolving mediators in the entorhinal cortex of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 were higher in AD

Martinsen A. et al., 2019 [70]

Animal study

APOE4 Female mice

Various SPMs

Brain postmortem tissue samples

↓ SPMs in mice with the APOE4 genotype

Emre C. et al., 2020 [71]

Human study

Patients with AD

SPMs receptors

Brain postmortem tissue samples

↑ SPMs receptors

Emre C, Do K V. et al., 2021 [67]

Animal study

APP KI mouse model of AD

LMs profile

Brain postmortem tissue samples

↑ microglia proliferation starting from a young age in the App KI mice, while ↓ astrocyte numbers in older ages

Brain lipidome appears to be modified preferentially during aging as compared to amyloid pathology, as the oldest age group was the one with the greatest increase in LMs, despite an early onset of Aβ pathology

Emre C, Arroyo-García et al., 2022 [72]

Animal study

Murine model of AD

RvE1, RvD1, RvD2, MaR1 and NPD1

Intranasal

Amelioration of memory deficits; restoration of Gamma oscillation deficits; ↓ microglial activation

Kantarci A. et al., 2017 [20]

Animal study

Murine model of AD

RvE1 and LXA4

Intraperitoneal

↑ RvE1, LXA4, and RvD2 in the hippocampus; reversing of the inflammatory process,

↓ neuroinflammation

Wu J. et al., 2011 [73]

Animal study

Murine model of AD

LXA4

Intracerebroventricular

Inhibiting the inflammatory response induced by β-amyloid in the cortex and hippocampus (in particular, production of IL-1b and TNFa)

Serhan CN., 2005 [74]

Animal study

Murine model of AD

ATL

Subcutaneous

 

↓ NF-kB activation and levels of proinflammatory cytokines and chemokines; creating an anti-inflammatory cerebral milieu, resulting in the recruitment of microglia in an alternative phenotype

Medeiros R. et al., 2013 [75]

 

Animal study

Murine model of AD

ATL

Subcutaneous

↓ phosphorylated-tau (p-tau)

Yin P. et al., 2019 [76]

 

Animal study

Murine model of AD

MaR1

Intracerebroventricular

Improving cognitive decline of experimental mice: attenuating microglial activation, ↓ the pro-inflammatory cytokines in favor of anti-inflammatory ones, and ↑ the levels of proteins related to survival pathway including PI3K/AKT, ERK; ↓ levels of proteins associated with inflammation, autophagy, and apoptosis pathways, such as p38, mTOR and caspase 3

Schröder N et al., 2020 [77]

Animal study

Murine model of AD

Ac2-26

Intraperitoneal injection

No beneficial effect

Park JC et al., 2017 [78]

In vitro and in vivo (animal study)

Aβ-42 treated murine brain endothelial cell line bEnd.3;

Murine model of AD

Human recombinant ANXA1; ANXA1

Administration of human recombinant ANXA1 in Aβ-42 treated murine brain endothelial cell line bEnd.3; ANXA1 levels on blood of murine model of AD

rescuing β-amyloid 1–42 -induced BBB disruption via inhibition of RhoA-ROCK signaling pathway in brain endothelial cell line bEnd.3;

↓ ANXA1 in a murine model of AD

Ries M. et al., 2021 [79]

Animal study

Murine model of AD

Human recombinant AnxA1

Intravenous injection

↓ β-amyloid load and p-tau build-up in 5xFAD mice and Tau-P301L mice; prolonged treatment reduced the memory deficits and increased synaptic density in young 5xFAD mice

Tian Y. et al., 2015 [80]

Animal study

Rat model of PD

RvD2

Intrathecal injection on substantia nigra pars compacta

recovering neural injury by suppressing inflammatory mediator expression

Krashia P. et al., 2019 [81]

Animal study

Rats overexpressing human α-synuclein (Syn)

RvD1

Chronic intraperitoneal injection

preventing central and peripheral inflammation, as well as neuronal dysfunction and motor deficits

* AD: Alzheimer Disease; Ac2-26: annexin/lipocortin 1-mimetic peptide; ATL: Aspirin-triggered LXA4; LXA4: Lipoxin A4; LMs: Lipid Mediators; MaR1: Maresin1; MCI: Mild cognitive impairment; N-AS: N-acetyl sphingosine; n3-PUFAs: omega-3 polyunsaturated fatty acids; NPD1: Neuroprotectin D1; PD: Parkinson Disease; RvD1: Resolvin D1; RvD4: Resolvin D4; RvD5: Resolvin D5; RvE1: Resolvin E1; SCI: Subjective cognitive impairment.

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