Implication of system xc- in neuroinflammation during the onset and maintenance of neuropathic pain.

BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.

Mitochondrial dysfunction and type I interferon signaling induce anxiodepressive-like behaviors in mice with neuropathic pain.

Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain; however, the cellular basis for chronic pain-mediated major depression remains unclear. Mitochondrial dysfunction induces neuroinflammation and has been implicated in various neurological diseases, including depression. Nevertheless, the relationship between mitochondrial dysfunction and anxiodepressive-like behaviors in the neuropathic pain state remains unclear. The current study examined whether hippocampal mitochondrial dysfunction and downstream neuroinflammation are involved in anxiodepressive-like behaviors in mice with neuropathic pain, which was induced by partial sciatic nerve ligation (PSNL). At 8 weeks after surgery, there was decreased levels of mitochondrial damage-associated molecular patterns, such as cytochrome c and mitochondrial transcription factor A, and increased level of cytosolic mitochondrial DNA in the contralateral hippocampus, suggesting the development of mitochondrial dysfunction. Type I interferon (IFN) mRNA expression in the hippocampus was also increased at 8 weeks after PSNL surgery. The restoration of mitochondrial function by curcumin blocked the increased cytosolic mitochondrial DNA and type I IFN expression in PSNL mice and improved anxiodepressive-like behaviors. Blockade of type I IFN signaling by anti-IFN alpha/beta receptor 1 antibody also improved anxiodepressive-like behaviors in PSNL mice. Together, these findings suggest that neuropathic pain induces hippocampal mitochondrial dysfunction followed by neuroinflammation, which may contribute to anxiodepressive-behaviors in the neuropathic pain state. Improving mitochondrial dysfunction and inhibiting type I IFN signaling in the hippocampus might be a novel approach to reducing comorbidities associated with neuropathic pain, such as depression and anxiety.

Neuroinflammation and COVID-19 Ischemic Stroke Recovery-Evolving Evidence for the Mediating Roles of the ACE2/Angiotensin-(1-7)/Mas Receptor Axis and NLRP3 Inflammasome.

Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1-7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.

Os impactos da neuroinflamação na doença de Alzheimer / The impacts of neuroinflamation on Alzheimer's disease

A Doença de Alzheimer (DA) consiste em um grande problema de saúde pública no Brasil e no mundo. Trata-se de uma doença neurodegenerativa, em que ocorre perda progressiva de neurônios e atrofia das regiões cerebrais. Essa degeneração está associada principalmente ao depósito de duas proteínas tóxicas: a proteína beta-amiloide e a proteína Tau, uma vez que estas proteínas se encontram acumuladas, elas prejudicam a ocorrência de sinapses nervosas. Apesar de extremamente prevalente na população mais idosa, suas causas ainda não estão bem esclarecidas, sendo que vários fatores já foram apontados como possíveis motivos para o surgimento do depósito destas proteínas, levando assim a neurodegeneração. Recentemente, tem se estudado o papel da inflamação, que é fundamental durante todo o curso da doença, tanto para a eliminação das proteínas tóxicas quanto para a proteção de neurônios. Um funcionamento anormal do processo inflamatório poderia dificultar a eliminação das proteínas e acentuar a perda neuronal. Com isso essa revisão de literatura tem como objetivo descrever os principais fatores imunológico que se encontram alterados na Doença de Alzheimer e como isso pode contribuir para o quadro neurodegenerativo.

Alzheimer's Disease (AD) is a major public health problem in Brazil and worldwide. It is a neurodegenerative disease, in which there is a progressive loss of neurons and atrophy of brain regions. This degeneration is mainly associated with the deposition of two toxic proteins, the beta-amyloid protein and the Tau protein, once these proteins are accumulated, they impair the occurrence of nerve synapses. Despite being extremely prevalent in the older population, its causes are still not well understood, and several factors have already been pointed out as possible reasons for the emergence of the deposit of these proteins, thus leading to neurodegeneration. Recently, the role of inflammation, which is fundamental throughout the course of the disease, has been studied, both for the elimination of toxic proteins and for the protection of neurons. An abnormal functioning of the inflammatory process could hinder the elimination of proteins and accentuate the neuronal loss Thus, this literature review aims to describe the main immunological factors that are altered in Alzheimer's Disease and how this can contribute to the neurodegenerative picture.

Evidence of Neuroinflammation and Blood-Brain Barrier Disruption in Women with Preeclampsia and Eclampsia.

Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood-brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and eclampsia. We included women recruited to the South African Preeclampsia Obstetric Adverse Events (PROVE) biobank. Blood and cerebrospinal fluid (CSF) were collected around delivery. CSF was analyzed for neuroinflammatory markers interleukin 1ß, interleukin 6, interleukin-8 and tumor necrosis factor alpha (TNF-alpha). The CSF to plasma albumin ratio was measured to assess blood-brain barrier function. Women with eclampsia (n = 4) showed increased CSF concentrations of all pro-inflammatory cytokines and TNF-alpha compared to women with normotensive pregnancies (n = 7) and also for interleukin-6 and TNF-alpha compared to women with preeclampsia (n = 4). Women with preeclampsia also showed increases in pro-inflammatory cytokines IL-6 and IL-8 but not TNF-alpha in the CSF compared to women with normotensive pregnancies. In particular, women with eclampsia but also women with preeclampsia showed an increase in the CSF to plasma albumin ratio compared to normotensive women. In conclusion, women with preeclampsia and eclampsia show evidence of neuroinflammation and an injured blood-brain barrier. These findings are seen in particular among women with eclampsia.

Myocardial infarction coincides with increased NOX2 and Nε-(carboxymethyl) lysine expression in the cerebral microvasculature.

BACKGROUND: Myocardial infarction (MI) is associated with mental health disorders, in which neuroinflammation and cerebral microvascular dysfunction may play a role. Previously, we have shown that the proinflammatory factors Nε-(carboxymethyl)lysine (CML) and NADPH oxidase 2 (NOX2) are increased in the human infarcted heart microvasculature. The aim of this study was to analyse the presence of CML and NOX2 in the cerebral microvasculature of patients with MI. METHODS: Brain tissue was obtained at autopsy from 24 patients with MI and nine control patients. According to their infarct age, patients with MI were divided into three groups: 3-6 hours old (phase I), 6 hours-5 days old (phase II) and 5-14 days old (phase III). CML and NOX2 in the microvasculature were studied through immunohistochemical analysis. RESULTS: We observed a 2.5-fold increase in cerebral microvascular CML in patients with phase II and phase III MI (phase II: 21.39±7.91, p=0.004; phase III: 24.21±10.37, p=0.0007) compared with non-MI controls (8.55±2.98). NOX2 was increased in microvessels in patients with phase II MI (p=0.002) and phase III MI (p=0.04) compared with controls. No correlation was found between CML and NOX2 (r=0.58, p=0.13). CONCLUSIONS: MI coincides with an increased presence of CML and NOX2 in the brain microvasculature. These data point to proinflammatory alterations in the brain microvasculature that may underlie MI-associated mental health disorders.

Luteolin Suppresses Microglia Neuroinflammatory Responses and Relieves Inflammation-Induced Cognitive Impairments.

Microglia-mediated neuroinflammation in response to injurious self and non-self-stimuli exerts detrimental effects on neurons, which may lead to cognitive impairment. Luteolin, a typical kind of natural flavonoid in honeysuckle, chrysanthemum, and Herba Schizonepetae, is widely recognized to be anti-inflammatory and antioxidant against peripheral inflammation. However, its protective effect against inflammation-induced cognitive impairment is currently unknown. In this paper, we investigated the relief potential of luteolin against lipopolysaccharide (LPS)-induced cognitive impairment and neuroinflammation and its possible anti-inflammatory mechanisms in lipopolysaccharide-stimulated BV2 microglia cells. In this study, luteolin ameliorated LPS-induced cognitive impairments, indicated by behavioral performance of neuroinflammatory model mice in Morris water maze tests. Protein analyses and histological examination also revealed protective effect of luteolin against neuronal damage, through inhibiting overproduction of inflammatory cytokines in both hippocampus and cortex of mice. We also observed luteolin in vitro significantly suppressed the levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 ß (IL-1ß), and inflammatory mediators like nitric oxide. Taken together, these results demonstrated luteolin was effective in alleviating cognitive impairment and limited neuronal damage via inhibiting the release of inflammatory mediators, suggesting luteolin is potential for further therapeutic research of neuroinflammation-related neurodegenerative diseases.

Cocaine augments neuro-inflammation via modulating extracellular vesicle release in HIV-1 infected immune cells.

BACKGROUND: Extracellular Vesicles (EV) recently have been implicated in the pathogenesis of HIV-1 syndromes, including neuroinflammation and HIV-1 associated neurological disorder (HAND). Cocaine, an illicit stimulant drug used worldwide is known to exacerbate these HIV-1 associated neurological syndromes. However, the effects of cocaine on EV biogenesis and roles of EVs in enhancing HIV-1 pathogenesis are not yet well defined. RESULTS: Here, we investigated the effects of cocaine on EV biogenesis and release in HIV-1 infected immune cells and explored their roles in elicitation of neuroinflammation. We found that cocaine significantly augmented the release of EVs from uninfected and HIV-1 infected T-cells, DCs and macrophages. Further analysis of the molecular components of EVs revealed enhanced expression of adhesion molecules integrin ß1 and LFA-1 in those EVs derived from cocaine treated cells. Intriguingly, in EVs derived from HIV-1 infected cells, cocaine treatment significantly increased the levels of viral genes in EVs released from macrophages and DCs, but not in T-cells. Exploring the molecular mechanism to account for this, we found that DCs and macrophages showed enhanced expression of the cocaine receptor Sigma 1-Receptor compared to T-cells. In addition, we found that cocaine significantly altered the integrity of the RNA-induced silencing complex (RISC) in HIV-1 infected macrophages and DCs compared to untreated HIV-1 infected cells. Characterizing further the molecular mechanisms involved in how cocaine increased EV release, we found that cocaine decreased the expression of the interferon-inducible protein BST-2; this resulted in altered trafficking of intracellular virus containing vesicles and EV biogenesis and release. We also observed EVs released from cocaine treated HIV-1 infected macrophages and DCs enhanced HIV-1 trans-infection to T-cells compared to those from untreated and HIV-1 infected cells. These EVs triggered release of proinflammatory cytokines in human brain microvascular endothelial cells (HBMECs) and altered monolayer integrity. CONCLUSIONS: Taken together, our results provide a novel mechanism which helps to elucidate the enhanced prevalence of neurological disorders in cocaine using HIV-1 infected individuals and offers insights into developing novel therapeutic strategies against HAND in these hosts.

Morin attenuates memory deficits in a rat model of Alzheimer's disease by ameliorating oxidative stress and neuroinflammation.

This study aimed to investigate the effect of flavonoid morin on oxidative/nitrosative stress, neuroinflammation, and histological, molecular, and behavioral changes caused by amyloid-beta (Aß)1-42 in male Wistar rats (Alzheimer's disease model). Rats received morin (20 mg/kg, oral gavage) for 14 consecutive days after intrahippocampal injection of Aß1-42. Morin decreased the levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced catalase activity in the hippocampus of animals receiving Aß1-42. It also reduced the expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, nuclear factor-kappa B, and N-methyl-D-aspartate receptor subunits 2A and 2B and increased the expression of brain-derived neurotrophic factor and α7 nicotinic acetylcholine receptor in the hippocampus of Aß1-42-injected rats. Besides, morin modified neuronal loss and histological changes in the CA1 region of the hippocampus. Morin allowed Aß1-42-infused rats to swim more time in the target quadrant in the Morris water maze test. It is concluded that morin may be suitable for the prevention and treatment of Alzheimer's disease by strengthening the antioxidant system, inhibiting neuroinflammation, preventing neuronal death, and enhancing memory function.