J Neuroimmune Pharmacol [JOURNAL]
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200 papers
Neuroprotective Effects of Dexamethasone in a Neuromelanin-Driven Parkinson's Disease Model.
Garcia-Gomara M, Juan-Palencia A, Alfaro M … +2 more , Cuadrado-Tejedor M, Garcia-Osta A
J Neuroimmune Pharmacol · 2024 Dec · PMID 39672994 · Full text
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra that primarily affects movement control. Neuroinflammation plays a pivotal role in driving the disease's p...
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra that primarily affects movement control. Neuroinflammation plays a pivotal role in driving the disease's progression. The persistent inflammatory state in the brain exacerbates neuronal damage, creating a cycle that perpetuates the neurodegenerative process. Glucocorticoids, such as dexamethasone, have potent anti-inflammatory properties and have been studied for their neuroprotective potential in different neurodegenerative diseases. However, their specific impact on PD remains unclear. This study aimed to evaluate the impact of dexamethasone on a neuromelanin (NM)-driven model of PD. We demonstrated that dexamethasone administration significantly improved motor function and preserved dopaminergic neuron compared to untreated controls in our study. These neuroprotective effects were mediated, at least in part, by suppressing reactive microglia and reducing the infiltration of peripheral immune cells into the brain. Our findings underscore the potential therapeutic benefits of dexamethasone in mitigating neuroinflammation and maintaining neuronal integrity in a NM-driven model of PD. These results advocate for further investigation into glucocorticoid-based therapies as adjunctive treatments for PD, particularly in scenarios where neuroinflammation contributes prominently to disease progression.
Protective Effects of Antcin H Isolated from Antrodia cinnamomea Against Neuroinflammation in Huntington's Disease via NLRP3 Inflammasome Inhibition.
Chang YJ, Chen CH, Chen YC … +4 more , Wu MT, Lin TY, Hua KF, Ju TC
J Neuroimmune Pharmacol · 2024 Dec · PMID 39621196 · Publisher ↗
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. When the CAG repeat exceeds 36, it results in the accumula...
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. When the CAG repeat exceeds 36, it results in the accumulation of the mutant HTT (mHTT) protein in neurons and glial cells. Key pathological mechanisms in HD include excitotoxicity, energy dysfunction, impaired mitochondrial function, increased oxidative stress, and neuroinflammation. The NLRP3 inflammasome is a multimeric protein complex element of NLRP3, ASC, and caspase-1, which regulates interleukin (IL)-1β and IL-18 secretion. The NLRP3 inflammasome plays an important role in inflammatory reactions and is involved in the pathogenesis of several neurodegenerative diseases. We have previously demonstrated high NLRP3 inflammasome expression levels in the striatum of R6/2 mice (a transgenic HD mouse model). Systematic administration of an NLRP3 inhibitor (MCC950) to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, suggesting protective effects against HD. Antrodia cinnamomea is an indigenous medicinal fungus in Taiwan, which shows diverse medicinal and pharmacological activities, but its effects in HD are not well understood. Herein, we report that systematic administration of Antcin-H isolated from A. cinnamomea to R6/2 mice suppressed the NLRP3 inflammasome, IL-1β production, and reduced neuronal toxicity. Most importantly, oral administration of Antcin-H reduced disease progression by increasing neuronal survival, reducing neuroinflammation during an extended lifespan, and improving motor dysfunction in R6/2 mice. Taken together, our data suggest that Antcin-H has therapeutic potential for treating HD.
Matrix Metalloproteinase-9 Signaling Regulates Colon Barrier Integrity in Models of HIV Infection.
Ohene-Nyako M, Persons AL, Forsyth C … +2 more , Keshavarzian A, Napier TC
J Neuroimmune Pharmacol · 2024 Nov · PMID 39499375 · Publisher ↗
Infection with human immunodeficiency virus (HIV) increases risk for maladies of the gut barrier, which promotes sustained systemic inflammation even in virally controlled patients. We previously revealed morphological d...
Infection with human immunodeficiency virus (HIV) increases risk for maladies of the gut barrier, which promotes sustained systemic inflammation even in virally controlled patients. We previously revealed morphological disorganization of colon epithelial barrier proteins in HIV-1 transgenic (Tg) rats. The current study evaluated mechanisms that may underlie gut barrier pathology induced by toxic HIV-1 proteins. Methamphetamine (meth) use is prevalent among HIV-infected individuals, and meth can exaggerate morbidity of HIV infection. Thus, we determined whether meth exposure worsened HIV-associated gut pathology using colon samples from HIV-1 Tg and non-Tg rats that self-administered meth 2 h/day for 21 days. Immunoblotting was conducted for occludin (a gut barrier protein) and matrix metalloproteinase-9 (MMP-9; a proteinase regulator of occludin). Colon levels of occludin were decreased, and MMP-9 levels and activity were increased in HIV-1 Tg rats. A Pearson correlation revealed an inverse relationship between occludin levels and MMP-9 activity. Doses of meth that were self-administered by Tg rats were lower than other rat models. Meth-induced trends in non-Tg rats were not significant, and meth did not exaggerate effects seen in Tg rats. Accordingly, only the HIV-effects on epithelial function were explored further. Transepithelial resistance (TER) across a monolayer of human colon epithelial cells (Caco-2) was used to examine treatments with the HIV-1 toxic protein, Tat, and the ability of pioglitazone, a PPARγ agonist that inhibits MMP-9, to mitigate Tat-induced changes. Exposure to Tat for 24 h decreased TER, which co-occurred with decreases in levels of barrier tight junction proteins (occludin, claudin-1, and zonula occludens-1) and with increases in the level and activity of MMP-9. Pretreatment or post-treatment with pioglitazone respectively prevented and restored Tat-induced impairments of Caco-2 barrier. Thus, while low doses of meth did not alter barrier proteins in the current study, exposure to HIV-1 proteins disrupted the gut barrier, and this action involved a dysregulation of MMP-9.
Vitamin K2 Ameliorates Diabetes-Associated Cognitive Decline by Reducing Oxidative Stress and Neuroinflammation.
Chatterjee K, Pal A, Padhy DS … +6 more , Saha R, Chatterjee A, Bharadwaj M, Sarkar B, Mazumder PM, Banerjee S
J Neuroimmune Pharmacol · 2024 Oct · PMID 39466454 · Publisher ↗
Diabetes, a chronic metabolic disease, affects approximately 422 million people and leads to 1.5 million deaths every year, It is found that 45% of individuals with diabetes eventually develop cognitive impairment. Here...
Diabetes, a chronic metabolic disease, affects approximately 422 million people and leads to 1.5 million deaths every year, It is found that 45% of individuals with diabetes eventually develop cognitive impairment. Here we study effects of Vitamin K2 on diabetes-associated cognitive decline (DACD) and its underlying mechanism. Diabetes was induced in adult Swiss albino mice with high-fat diet and a low dose (35 mg/kg) of streptozotocin and measured by fasting glucose and HbA1c levels. After one week of development of diabetes, one group of animals received Vitamin K2 (100 µg/kg) via oral gavage for 21 days. Then different behavioural studies, including the elevated plus maze, Morris water maze, passive avoidance test and novel object recognition test were performed followed by biochemical tests including AchE, different oxidative stress parameters (SOD, GSH, MDA, catalase, SIRT1, NRF2), inflammatory markers (TNFα, IL1β, MCP1, NFκB), apoptosis marker (Caspase 3). Hippocampal neuronal density was measured using histopathology. Vitamin K2 treatment in diabetic animals led to reduced fasting glucose and HbA1c, It could partially reverse DACD as shown by behavioural studies. Vitamin K2 adminstration reduced corticohippocampal AchE level and neuroinflammation (TNFα, IL1β, MCP1, NFκB, SIRT1). It reduced oxidative stress by increasing antioxidant enzymes (SOD, GSH, catalase), transcription factor NRF2 while reducing caspase 3. This eventually increased CA1 and CA3 neuronal density in diabetic animals. Vitamin K2 partially reverses DACD by increasing ACh while reducing the oxidative stress via Nrf2/ARE pathway and neuroinflammation, thus protecting the hippocampal neurons from diabetes associated damage.
Exosomes Derived from DPA-treated UCMSCs Attenuated Depression-like Behaviors and Neuroinflammation in a Model of Depression Induced by Chronic Stress.
Li P, Zhang F, Huang C … +4 more , Zhang C, Yang Z, Zhang Y, Song C
J Neuroimmune Pharmacol · 2024 Oct · PMID 39432176 · Publisher ↗
Depression is characterized by both neuroinflammation and neurodegeneration. Exosomes (Exo) have been shown to function as inhibitors of inflammation and promoters of neurogenesis. Omega-3 polyunsaturated fatty acids, su...
Depression is characterized by both neuroinflammation and neurodegeneration. Exosomes (Exo) have been shown to function as inhibitors of inflammation and promoters of neurogenesis. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid, can combat depression by increasing levels of docosapentaenoic acid (DPA). This study explored the effects of DPA on the therapeutic potential of Exo derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in glia-induced neuroinflammation associated with depression. Exposure to chronic unpredictable mild stress (CUMS) over six weeks induced depression- and anxiety-like behaviors, while decreasing the levels of serotonin and dopamine. Molecularly, CUMS increased the concentrations of the microglial M1 markers Iba1, iNOS, and IL-1β, while reducing the M2 markers Arg1, CD206, and IL-10 in the prefrontal cortex and hippocampus. However, Exo therapy reversed these effects. Moreover, DPA treatment of Exo demonstrated superior efficacy in alleviating depressive behaviors, neurotransmitter deficiencies, and M1 microglial activation. In vitro, Exo suppressed LPS-stimulated BV2 cell viability and M1 microglial activation, while mitigating the SH-SY5Y cell apoptosis triggered by treatment with the conditioned medium from LPS-activated BV2 cells. Furthermore, administration of DPA enhanced this effect. Mechanically, DPA enhanced Exo function by upregulating miR125b-5p expression, thereby targeting the MyD88/TRAF6/NF-κB signaling pathway. In summary, Exo exhibited antidepressant effects by suppressing M1 microglial neuroinflammation, while DPA treatment provided a more potent therapeutic effect on depression-like changes through the upregulation of miR125b-5p targeting the MyD88/TRAF6/NF-κB pathway.
Soluble Epoxide Hydrolase Inhibitor Ameliorates Olfactory Dysfunction, Modulates Microglia Polarization, and Attenuates Neuroinflammation after Ischemic Brain Injury.
Yeh CF, Chuang TY, Lan MY … +3 more , Lin YY, Huang WH, Hung YW
J Neuroimmune Pharmacol · 2024 Oct · PMID 39417923 · Publisher ↗
Olfactory bulb (OB) microglia activation and inflammation can lead to olfactory dysfunction, which often occurs after an ischemic stroke. Inhibition of soluble epoxide hydrolase (sEH) attenuates neuroinflammation in brai...
Olfactory bulb (OB) microglia activation and inflammation can lead to olfactory dysfunction, which often occurs after an ischemic stroke. Inhibition of soluble epoxide hydrolase (sEH) attenuates neuroinflammation in brain injuries by reducing the degradation of anti-inflammatory epoxyeicosatrienoic acids. However, whether sEH inhibitors can ameliorate olfactory dysfunction after an ischemic stroke remains unknown. Ischemic brain injury and olfactory dysfunction were induced by middle cerebral artery occlusion (MCAO) in Wistar Kyoto rats. The rats were administered 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a selective sEH inhibitor. Olfactory function, cerebral infarct volume, and the degree of degeneration, microglial polarization and neuroinflammation in OB were evaluated. Following treatment with AUDA, rats subjected to MCAO displayed mild cerebral infarction and OB degeneration, as well as better olfactory performance. In OB, AUDA triggered a modulation of microglial polarization toward the M2 anti-inflammatory type, reduction in proinflammatory mediators, and enhancement of the antioxidant process. The effectiveness of AUDA in terms of anti-inflammatory, neuroprotection and anti-oxidative properties suggests that it may have clinical therapeutic implication for ischemic stroke related olfactory dysfunction.
Trifluoro-Icaritin Ameliorates Neuroinflammation Against Complete Freund's Adjuvant-Induced Microglial Activation by Improving CB2 Receptor-Mediated IL-10/β-endorphin Signaling in the Spinal Cord of Rats.
Liu G, Jia D, Li W … +3 more , Huang Z, Shan R, Huang C
J Neuroimmune Pharmacol · 2024 Oct · PMID 39387998 · Publisher ↗
The underlying pathogenesis of chronic inflammatory pain is greatly complex, but the relevant therapies are still unavailable. Development of effective candidates for chronic inflammatory pain is highly urgent. We previo...
The underlying pathogenesis of chronic inflammatory pain is greatly complex, but the relevant therapies are still unavailable. Development of effective candidates for chronic inflammatory pain is highly urgent. We previously identified that trifluoro-icaritin (ICTF) exhibited a significant therapeutic activity against complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, however, the precise mechanisms remain elusive. Here, the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis were used to determine the pain-related behaviors. The expression and co-localization of pain-related signaling molecules were detected by Western blot and immunofluorescence staining. Our results demonstrated that ICTF (3.0 mg/kg, i.p.) effectively attenuated mechanical allodynia, thermal hyperalgesia and improved motor dysfunction induced by CFA, and the molecular docking displayed that CB2 receptor may be the therapeutic target of ICTF. Furthermore, ICTF not only up-regulated the levels of CB2 receptor, IL-10, β-endorphin and CD206, but also reduced the expression of P2Y12 receptor, NLRP3, ASC, Caspase-1, IL-1β, CD11b, and iNOS in the spinal cord of CFA rats. Additionally, the immunofluorescence staining from the spinal cord showed that ICTF significantly increased the co-expression between the microglial marker Iba-1 and CB2 receptor, IL-10, β-endorphin, respectively, but markedly decreased the co-localization between Iba-1 and P2Y12 receptor. Conversely, intrathecal administration of CB2 receptor antagonist AM630 dramatically reversed the inhibitory effects of ICTF on CFA-induced chronic inflammatory pain, leading to a promotion of pain hypersensitivity, abnormal gait parameters, microglial activation, and up-regulation of P2Y12 receptor and NLRP3 inflammasome, as well as the inhibition of CB2 receptor and IL-10/β-endorphin cascade. Taken together, these findings highlighted that ICTF alleviated CFA-induced neuroinflammation by enhancing CB2 receptor-mediated IL-10/β-endorphin signaling and suppressing microglial activation in the spinal cord, and uncovered that CB2 receptor may be exploited as a novel and promising target for ICTF treatment of chronic inflammatory pain.
Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.
Izquierdo-Altarejos P, Martínez-García M, Atienza-Pérez I … +4 more , Hernández A, Moreno-Manzano V, Llansola M, Felipo V
J Neuroimmune Pharmacol · 2024 Oct · PMID 39382610 · Publisher ↗
Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE...
Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFβ in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.
Blocking Brain Myeloid Differentiation Factor 2-Toll-like Receptor 4 Signaling Improves Cognition by Diminishing Brain Pathologies and Preserving Adult Hippocampal Neurogenesis in Obese Rats.
Oo TT, Sumneang N, Chunchai T … +5 more , Apaijai N, Pratchayasakul W, Liang G, Chattipakorn N, Chattipakorn SC
J Neuroimmune Pharmacol · 2024 Oct · PMID 39373789 · Publisher ↗
The myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) signaling pathway has been linked to cognitive decline in obese rats. However, more research is required to fully understand the mechanistic role of...
The myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) signaling pathway has been linked to cognitive decline in obese rats. However, more research is required to fully understand the mechanistic role of MD-2-TLR4 signalling pathway in obese-related cognitive impairment. In this study, we used two novel MD-2 inhibitors-MAC28 (a mono-carbonyl analogue of curcumin 28) and 2i-10 (a cinnamamide-derivative compound)-to better comprehend the mechanistic role of the MD-2-TLR4 signalling pathway in obese-related cognitive impairment. A normal diet (ND) (n = 16) and a high-fat diet (HFD) (n = 64) were given to randomly divided groups of male Wistar rats for 16-weeks. At week 13, 2 types of vehicles were randomly administered to ND-fed and HFD-fed rats, whereas MAC28 (3-doses) and 2i-10 (3-doses) were randomly given to HFD-fed rats until week 16. HFD-fed rats developed obesity with metabolic disturbances, a variety of brain pathologies and cognitive decline. In obese rats, blocking the brain MD-2-TLR4 signalling pathway with MAC28 or 2i-10 improved cognition via reducing brain inflammation, neurodegeneration, microglial activation, dendritic spine loss, brain oxidative stress, as well as preserving adult hippocampal neurogenesis. Our findings highlight to better understand the role of MD-2-TLR4 signaling pathway in obese-related cognitive decline, and MD-2 could be a potential therapeutic target for brain pathologies and cognitive decline in obesity.
Targeting Toll-like Receptor 4/Nuclear Factor-κB and Nrf2/Heme Oxygenase-1 Crosstalk via Trimetazidine Alleviates Lipopolysaccharide-Induced Depressive-like Behaviors in Mice.
Mohamed SS, Rasheed NOA, Ibrahim WW … +1 more , Shiha NA
J Neuroimmune Pharmacol · 2024 Sep · PMID 39312021 · Full text
Depression is a global psychiatric illness that imposes a substantial economic burden. Unfortunately, traditional antidepressants induce many side effects which limit patient compliance thus, exploring alternative therap...
Depression is a global psychiatric illness that imposes a substantial economic burden. Unfortunately, traditional antidepressants induce many side effects which limit patient compliance thus, exploring alternative therapies with fewer adverse effects became urgent. This study aimed to investigate the effect of trimetazidine (TMZ); a well-known anti-ischemic drug in lipopolysaccharide (LPS) mouse model of depression focusing on its ability to regulate toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) as well as nuclear factor erythroid 2 related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathways. Male Swiss albino mice were injected with LPS (500 µg/kg, i.p) every other day alone or parallel with oral doses of either escitalopram (Esc) (10 mg/kg/day) or TMZ (20 mg/kg/day) for 14 days. Treatment with TMZ attenuated LPS-induced animals' despair with reduced immobility time inforced swimming test. TMZ also diminished LPS- induced neuro-inflammation via inhibition of TLR4/NF-κB pathway contrary to Nrf2/HO-1 cascade activation with consequent increase in reduced glutathione (GSH) and HO-1 levels whereas the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β were evidently reduced. Besides, TMZ replenished brain serotonin levels via serotonin transporter (SERT) inhibition. Thus, TMZ hindered LPS-induced neuro-inflammation, oxidative stress, serotonin deficiency besides its anti-apoptotic effect which was reflected by decreased caspase-3 level. Neuroprotective effects of TMZ were confirmed by the histological photomicrographs which showed prominent neuronal survival. Here we showed that TMZ is an affluent nominee for depression management via targeting TLR4/NF-κB and Nrf2/HO-1 pathways. Future research addressing TMZ-antidepressant activity in humans is mandatory to enroll it as a novel therapeutic strategy for depression.
MFG-E8 Ameliorates Nerve Injury-Induced Neuropathic Pain by Regulating Microglial Polarization and Neuroinflammation via Integrin β3/SOCS3/STAT3 Pathway in Mice.
Zhang L, Dai X, Li D … +7 more , Wu J, Gao S, Song F, Liu L, Zhou Y, Liu D, Mei W
J Neuroimmune Pharmacol · 2024 Sep · PMID 39305375 · Publisher ↗
Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG...
Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin β3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin β3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin β3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain.
Tetramerization of PKM2 Alleviates Traumatic Brain Injury by Ameliorating Mitochondrial Damage in Microglia.
Zhu H, Zhang H, Zhao XJ … +5 more , Zhang L, Liu X, Zhang ZY, Ren YZ, Feng Y
J Neuroimmune Pharmacol · 2024 Aug · PMID 39196455 · Publisher ↗
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive...
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive function. Studies have suggested that the metabolic characteristics of microglia dictate their inflammatory response. The pyruvate kinase isoform M2 (PKM2), a key glycolytic enzyme, is involved in the regulation of various cellular metabolic processes, including mitochondrial metabolism. This suggests that PKM2 may also participate in the regulation of microglial activation during TBI. Therefore, the present study aimed to evaluate the role of PKM2 in regulating microglial activation and neuroinflammation and its effects on cognitive function following TBI. A controlled cortical impact (CCI) mouse model and inflammation-induced primary mouse microglial cells in vitro were used to investigate the potential effects of PKM2 inhibition and regulation. PKM2 was significantly increased during the acute and subacute phases of TBI and was predominantly detected in microglia rather than in neurons. Our results demonstrate that shikonin and TEPP-46 can inhibit microglial inflammation, improving mitochondria, improving mouse behavior, reducing brain defect volume, and alleviating pathological changes after TBI. There is a difference in the intervention of shikonin and TEPP-46 on PKM2. Shikonin directly inhibits General PKM2; TEPP-46 can promote the expression of PKM2 tetramer. In vitro experiments, TEPP-46 can promote the expression of PKM2 tetramer, enhance the interaction between PKM2 and MFN2, improve mitochondria, alleviate neuroinflammation. General inhibition and tetramerization activation of PKM2 attenuated cognitive function caused by TBI, whereas PKM2 tetramerization exhibited a better treatment effect. Our experiments demonstrated the non-metabolic role of PKM2 in the regulation of microglial activation following TBI. Both shikonin and TEPP-46 can inhibit pro-inflammatory factors, but only TEPP-46 can promote PKM2 tetramerization and upregulate the release of anti-inflammatory factors from microglia.
T Cells Trafficking into the Brain in Aging and Alzheimer's Disease.
Ma YZ, Cao JX, Zhang YS … +3 more , Su XM, Jing YH, Gao LP
J Neuroimmune Pharmacol · 2024 Aug · PMID 39180590 · Publisher ↗
The meninges, choroid plexus (CP) and blood-brain barrier (BBB) are recognized as important gateways for peripheral immune cell trafficking into the central nervous system (CNS). Accumulation of peripheral immune cells i...
The meninges, choroid plexus (CP) and blood-brain barrier (BBB) are recognized as important gateways for peripheral immune cell trafficking into the central nervous system (CNS). Accumulation of peripheral immune cells in brain parenchyma can be observed during aging and Alzheimer's disease (AD). However, the mechanisms by which peripheral immune cells enter the CNS through these three pathways and how they interact with resident cells within the CNS to cause brain injury are not fully understood. In this paper, we review recent research on T cells recruitment in the brain during aging and AD. This review focuses on the possible pathways through which T cells infiltrate the brain, the evidence that T cells are recruited to the brain, and how infiltrating T cells interact with the resident cells in the CNS during aging and AD. Unraveling these issues will contribute to a better understanding of the mechanisms of aging and AD from the perspective of immunity, and hopefully develop new therapeutic strategies for brain aging and AD.
Sigma-1 Receptors Control Neuropathic Pain and Peripheral Neuroinflammation After Nerve Injury in Female Mice: A Transcriptomic Study.
Ruiz-Cantero MC, Entrena JM, Artacho-Cordón A … +7 more , Huerta MÁ, Portillo-Salido E, Nieto FR, Baeyens JM, Costigan M, González-Cano R, Cobos EJ
J Neuroimmune Pharmacol · 2024 Aug · PMID 39162886 · Publisher ↗
The mechanisms for neuropathic pain amelioration by sigma-1 receptor inhibition are not fully understood. We studied genome-wide transcriptomic changes (RNAseq) in the dorsal root ganglia (DRG) from wild-type and sigma-1...
The mechanisms for neuropathic pain amelioration by sigma-1 receptor inhibition are not fully understood. We studied genome-wide transcriptomic changes (RNAseq) in the dorsal root ganglia (DRG) from wild-type and sigma-1 receptor knockout mice prior to and following Spared Nerve Injury (SNI). In wildtype mice, most of the transcriptomic changes following SNI are related to the immune function or neurotransmission. Immune function transcripts contain cytokines and markers for immune cells, including macrophages/monocytes and CD4 + T cells. Many of these immune transcripts were attenuated by sigma-1 knockout in response to SNI. Consistent with this we found, using flow cytometry, that sigma-1 knockout mice showed a reduction in macrophage/monocyte recruitment as well as an absence of CD4 + T cell recruitment in the DRG after nerve injury. Sigma-1 knockout mice showed a reduction of neuropathic (mechanical and cold) allodynia and spontaneous pain-like responses (licking of the injured paw) which accompany the decreased peripheral neuroinflammatory response after nerve injury. Treatment with maraviroc (a CCR5 antagonist which preferentially inhibits CD4 + T cells in the periphery) of neuropathic wild-type mice only partially replicated the sigma-1 knockout phenotype, as it did not alter cold allodynia but attenuated spontaneous pain-like responses and mechanical hypersensitivity. Therefore, modulation of peripheral CD4 + T cell activity might contribute to the amelioration of spontaneous pain and neuropathic tactile allodynia seen in the sigma-1 receptor knockout mice, but not to the effect on cold allodynia. We conclude that sigma-1 receptor inhibition decreases DRG neuroinflammation which might partially explain its anti-neuropathic effect.
The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.
Duarte-Silva E, Oriá AC, Mendonça IP … +7 more , Paiva IHR, Leuthier Dos Santos K, Sales AJ, de Souza JRB, Maes M, Meuth SG, Peixoto CA
J Neuroimmune Pharmacol · 2024 Aug · PMID 39158758 · Publisher ↗
Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and...
Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.
Hyperalgesic Effect Evoked by il-16 and its Participation in Inflammatory Hypernociception in Mice.
González-Rodríguez S, Sordo-Bahamonde C, Álvarez-Artime A … +2 more , Baamonde A, Menéndez L
J Neuroimmune Pharmacol · 2024 Aug · PMID 39152360 · Full text
The systemic administration of interleukin-16 (IL-16, 3-30 ng/kg) induced thermal hyperalgesia in mice, that was prevented by the acute injection of an anti-CD4 antibody (1 µg/kg), the depletion of circulating white bloo...
The systemic administration of interleukin-16 (IL-16, 3-30 ng/kg) induced thermal hyperalgesia in mice, that was prevented by the acute injection of an anti-CD4 antibody (1 µg/kg), the depletion of circulating white blood cells by cyclophosphamide or the specific reduction of circulating CD4 cells provoked by a high dose of an anti-CD4 antibody (30 µg/mouse, 24 h before). IL-16-induced hyperalgesia was locally inhibited after intraplantar (i.pl.) administration of the non-selective cyclooxygenase (COX) inhibitor diclofenac, the COX-1 inhibitor SC-560, the COX-2 inhibitor celecoxib, the TRPV1 antagonist capsazepine or the TRPA1 antagonist HC030031, thus demonstrating that prostaglandins and TRP channels are involved in this effect. The i.pl. administration of low doses of IL-16 (0.1-1 ng) evoked local hyperalgesia suggesting the possibility that IL-16 could participate in hypernociception associated to local tissue injury. Accordingly, IL-16 concentration measured by ELISA was increased in paws acutely inflamed with carrageenan or chronically inflamed with complete Freund´s adjuvant (CFA). This augmentation was reduced after white cell depletion with cyclophosphamide or neutrophil depletion with an anti-Ly6G antibody. Immunofluorescence and flow cytometry experiments showed that the increased concentration of IL-16 levels found in acutely inflamed paws is mainly related to the infiltration of IL-16 neutrophils, although a reduced number of IL-16 lymphocytes was also detected in paws inflamed with CFA. Supporting the functional role of IL-16 in inflammatory hypernociception, the administration of an anti-IL-16 antibody dose-dependently reduced carrageenan- and CFA-induced thermal hyperalgesia and mechanical allodynia. The interest of IL-16 as a target to counteract inflammatory pain is suggested.
Intestinal Akkermansia muciniphila is Beneficial to Functional Recovery Following Ischemic Stroke.
Li K, Ding W, Li X … +5 more , Gao H, Wang S, Li T, Zhao H, Zhang S
J Neuroimmune Pharmacol · 2024 Aug · PMID 39141019 · Publisher ↗
Recent studies have demonstrated the interaction between gut microbiota and brain on ischemic stroke, but the roles of gut microbiota in the pathophysiology of ischemic stroke remain largely unclear. In this study, we de...
Recent studies have demonstrated the interaction between gut microbiota and brain on ischemic stroke, but the roles of gut microbiota in the pathophysiology of ischemic stroke remain largely unclear. In this study, we detected a significant increase of intestinal Akkermansia muciniphila (AKK) following ischemic stroke by a rose bengal photothrombosis model. To investigate the function and mechanism of AKK on ischemic stroke, we performed the AKK administration prior to stroke surgery. The results showed that mice treated with AKK gained significantly higher body weight and behaved better than those in PBS group at 3 days after ischemic stroke. Consistently, AKK administration remarkably decreased the infarct volumes as well as the density of degenerating neurons and apoptotic cells after ischemic stroke. Notably, AKK is a potential therapeutic target in immune-related disorders connected to the microbiota, and inflammation is crucially involved in the pathophysiological process of ischemic stroke. For the determination of underlying mechanisms of this protective effect, we investigated whether there are associations between AKK and neuroinflammation following ischemic stroke. The results suggested that AKK administration significantly reduced the activation of astrocytes and microglia but up-regulated multiple anti-inflammatory factors following ischemic stroke. Therefore, our study highlighted the beneficial roles of intestinal AKK on ischemic stroke and provided a new perspective for the treatment of ischemic stroke.
Correction: FTY720 Inhibits MPP-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation.
Yao S, Li L, Sun X … +6 more , Hua J, Zhang K, Hao L, Liu L, Shi D, Zhou H
J Neuroimmune Pharmacol · 2024 Aug · PMID 39105974 · Publisher ↗
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Nrf1 Reduces COX-2 Expression and Maintains Cellular Homeostasis After Cerebral Ischemia/Reperfusion By Targeting IL-6/TNF-α Protein Production.
Yang J, Yang J, Luo Y … +5 more , Ran D, Xia R, Zheng Q, Yao P, Wang H
J Neuroimmune Pharmacol · 2024 Aug · PMID 39103507 · Publisher ↗
Neuroinflammation has been considered involved in the process of cerebral ischemia-reperfusion injury (CIRI). Transcription factors play a crucial role in regulating gene transcription and the expressions of specific pro...
Neuroinflammation has been considered involved in the process of cerebral ischemia-reperfusion injury (CIRI). Transcription factors play a crucial role in regulating gene transcription and the expressions of specific proteins during the progression of various neurological diseases. Evidence showed that transcription factor nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as Nrf1) possessed strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in CIRI remain unclear. In our study, we observed a significant elevation of Nrf1 in the cerebral cortex following cerebral ischemia-reperfusion in rats. The Nrf1 downregulation markedly raised COX-2, TNF-α, IL-1β, and IL-6 protein levels during middle cerebral artery occlusion/reperfusion in rats, which led to worsened neurological deficits, higher cerebral infarct volume, and intensified cortical histopathological damage. In subsequent in vitro studies, the expression of Nrf1 protein increased following oxygen-glucose deprivation/reperfusion treatment on neurons. Subsequently, Nrf1 knockdown resulted in a significant upregulation of inflammatory factors, leading to a substantial increase in the cell death rate. Through analyzing the alterations in the expression of inflammatory factors under diverse interventions, it is indicated that Nrf1 possesses the capacity to discern variations in inflammatory factors via specific structural domains. Our findings demonstrate the translocation of the Nrf1 protein from the cytoplasm to the nucleus, thereby modulating the protein expression of IL-6/TNF-α and subsequently reducing the expression of multiple inflammatory factors. This study signifies, for the first time, that during cerebral ischemia-reperfusion, Nrf1 translocases to the nucleus to regulate the protein expression of IL-6/TNF-α, consequently suppressing COX-2 expression and governing cellular inflammation, ultimately upholding cellular homeostasis.
Investigations on the Ability of the Insular Cortex to Process Peripheral Immunosuppression.
Bihorac J, Salem Y, Lückemann L … +7 more , Schedlowski M, Doenlen R, Engler H, Mark MD, Dombrowski K, Spoida K, Hadamitzky M
J Neuroimmune Pharmacol · 2024 Jul · PMID 39078442 · Full text
The brain and immune system communicate through complex bidirectional pathways, but the specificity by which the brain perceives or even remembers alterations in immune homeostasis is still poorly understood. Recent data...
The brain and immune system communicate through complex bidirectional pathways, but the specificity by which the brain perceives or even remembers alterations in immune homeostasis is still poorly understood. Recent data revealed that immune-related information under peripheral inflammatory conditions, termed as "immunengram", were represented in specific neuronal ensembles in the insular cortex (IC). Chemogenetic reactivation of these neuronal ensembles was sufficient to retrieve the inflammatory stages, indicating that the brain can store and retrieve specific immune responses. Against this background, the current approach was designed to investigate the ability of the IC to process states of immunosuppression pharmacologically induced by the mechanistic target of rapamycin (mTOR) inhibitor rapamycin. We here show that the IC perceives the initial state of immunosuppression, reflected by increased deep-brain electroencephalography (EEG) activity during acute immunosuppressive drug treatment. Following an experienced period of immunosuppression, though, diminished splenic cytokine production as formerly induced by rapamycin could not be reinstated by nonspecific chemogenetic activation or inhibition of the IC. These findings suggest that the information of a past, or experienced status of pharmacologically induced immunosuppression is not represented in the IC. Together, the present work extends the view of immune-to-brain communication during the states of peripheral immunosuppression and foster the prominent role of the IC for interoception.
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