RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is a valuable herb in traditional Chinese medicine. Modern research has shown that it has various benefits, including tonifying vital energy, nourishing and strengthening the body, calming the mind, improving cognitive function, regulating fluids, and returning blood pressure, etc. Rg1 is a primary active component of ginseng. It protects hippocampal neurons, improves synaptic plasticity, enhances cognitive function, and boosts immunity. Furthermore, it exhibits anti-aging and anti-fatigue properties and holds great potential for preventing and managing neurodegenerative diseases (NDDs). AIM OF THE STUDY: The objective of this study was to examine the role of Rg1 in treating chronic inflammatory NDDs and its molecular mechanisms. MATERIALS AND METHODS: In vivo, we investigated the protective effects of Rg1 against chronic neuroinflammation and cognitive deficits in mice induced by 200 µg/kg lipopolysaccharide (LPS) for 21 days using behavioral tests, pathological sections, Western blot, qPCR and immunostaining. In vitro experiments involved the stimulation of HT22 cells with 10 µg/ml of LPS, verification of the therapeutic effect of Rg1, and elucidation of its potential mechanism of action using H2DCFDA staining, BODIPY™ 581/591 C11, JC-1 staining, Western blot, and immunostaining. RESULTS: Firstly, it was found that Rg1 significantly improved chronic LPS-induced behavioral and cognitive dysfunction in mice. Further studies showed that Rg1 significantly attenuated LPS-induced neuronal damage by reducing levels of IL-6, IL-1ß and ROS, and inhibiting AIM2 inflammasome. Furthermore, chronic LPS exposure induced the onset of neuronal ferroptosis by increasing the lipid peroxidation product MDA and regulating the ferroptosis-associated proteins Gpx4, xCT, FSP1, DMT1 and TfR, which were reversed by Rg1 treatment. Additionally, Rg1 was found to activate Nrf2 and its downstream antioxidant enzymes, such as HO1 and NQO1, both in vivo and in vitro. In vitro studies also showed that the Nrf2 inhibitor ML385 could inhibit the anti-inflammatory, antioxidant, and anti-ferroptosis effects of Rg1. CONCLUSIONS: This study demonstrated that Rg1 administration ameliorated chronic LPS-induced cognitive deficits and neuronal ferroptosis in mice by inhibiting neuroinflammation and oxidative stress. The underlying mechanisms may be related to the inhibition of AIM2 inflammasome and activation of Nrf2 signaling. These findings provide valuable insights into the treatment of chronic neuroinflammation and associated NDDs.
Asunto(s)
Disfunción Cognitiva , Ferroptosis , Ginsenósidos , Neuronas , Transducción de Señal , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Línea Celular , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Proteínas de Unión al ADN , Ferroptosis/efectos de los fármacos , Ginsenósidos/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Microwave radiation (MWR) has been linked to neurodegeneration by inducing oxidative stress in the hippocampus of brain responsible for learning and memory. Ashwagandha (ASW), a medicinal plant is known to prevent neurodegeneration and promote neuronal health. This study investigated the effects of MWR and ASW on oxidative stress and cholinergic imbalance in the hippocampus of adult male Japanese quail. One control group received no treatment, the second group quails were exposed to MWR at 2 h/day for 30 days, third was administered with ASW root extract orally 100 mg/day/kg body weight and the fourth was exposed to MWR and also treated with ASW. The results showed that MWR increased serum corticosterone levels, disrupted cholinergic balance and induced neuro-inflammation. This neuro-inflammation further led to oxidative stress, as evidenced by decreased activity of antioxidant enzymes SOD, CAT and GSH. MWR also caused a significant decline in the nissil substances in the hippocampus region of brain indicating neurodegeneration through oxidative stress mediated hippocampal apoptosis. ASW, on the other hand, was able to effectively enhance the cholinergic balance and subsequently lower inflammation in hippocampus neurons. This suggests that ASW can protect against the neurodegenerative effects of MWR. ASW also reduced excessive ROS production by increasing the activity of ROS-scavenging enzymes. Additionally, ASW prevented neurodegeneration through decreased expression of caspase-3 and caspase-7 in hippocampus, thus promoting neuronal health. In conclusion, this study showed that MWR induces apoptosis and oxidative stress in the brain, while ASW reduces excessive ROS production, prevents neurodegeneration and promotes neuronal health.
Asunto(s)
Acetilcolinesterasa , Apoptosis , Coturnix , Hipocampo , Microondas , Estrés Oxidativo , Extractos Vegetales , Animales , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de la radiación , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Acetilcolinesterasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Enfermedades Neuroinflamatorias/prevención & control , Enfermedades Neuroinflamatorias/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Neuroinflammation represents a critical immune response within the brain, playing a pivotal role in defense against injury and infection. However, when this response becomes chronic, it can contribute to the development of various neurodegenerative and psychiatric disorders. This bibliographic review delves into the role of vitamin D in modulating neuroinflammation and its implications for brain health, particularly in the context of neurological and psychiatric disorders. While vitamin D is traditionally associated with calcium homeostasis and bone health, it also exerts immunomodulatory and neuroprotective effects within the central nervous system. Through comprehensive analysis of preclinical and clinical studies, we uncover how vitamin D, acting through its receptors in glial cells, may influence the production of proinflammatory cytokines and antioxidants, potentially mitigating the cascade of events leading to neuronal damage. Clinical research has identified vitamin D deficiency as a common thread in the increased risks of multiple sclerosis, Parkinson's disease, Alzheimer's, and depression, among others. Furthermore, preclinical models suggest vitamin D's regulatory capacity over inflammatory mediators, its protective role against neuronal apoptosis, and its contribution to neurogenesis and synaptic plasticity. These insights underscore the potential of vitamin D supplementation not only in slowing the progression of neurodegenerative diseases but also in improving the quality of life for patients suffering from psychiatric conditions. Future clinical studies are essential to validate these findings and further our understanding of vitamin D's capacity to prevent or alleviate symptoms, opening new avenues for therapeutic strategies against neuroinflammation-related pathologies. Neuroinflammation is a crucial immune response in the brain against injuries or infections, but its persistence can lead to diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and depression. Cholecalciferol (Vitamin D3) emerges as a regulator of neuroinflammation, present in brain cells such as astrocytes and microglia, modulating immune function. Vitamin D's mechanisms of action include cytokine modulation and regulation of nuclear and mitochondrial genes. It adjusts inflammatory mediators and antioxidants, resulting in neuroprotective effects. Additionally, vitamin D impacts neurotransmitter synthesis and brain plasticity. This positions vitamin D as a potential adjunct in treating diseases like Alzheimer's and Parkinson's. Lastly, its role in intestinal microbiota and serotonin synthesis contributes to psychiatric disorders like schizophrenia and depression. Thus, vitamin D presents a novel therapeutic approach for neuroinflammatory, neurodegenerative, and neuropsychiatric diseases.
Asunto(s)
Encéfalo , Enfermedades Neuroinflamatorias , Vitamina D , Humanos , Vitamina D/metabolismo , Vitamina D/farmacología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Animales , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/inmunologíaRESUMEN
BACKGROUND: Oxidative stress and inflammatory responses play essential roles in cerebral ischemia/reperfusion (I/R) injury. Electroacupuncture (EA) is widely used as a rehabilitation method for stroke in China; however, the underlying mechanism of action remains unclear. Peroxisome proliferator-activated receptor gamma (PPAR-γ) has been reported to impact anti-inflammatory and anti-oxidative effects. OBJECTIVE: This study investigated the role of PPAR-γ in EA-mediated effects and aimed to illuminate its possible mechanisms in cerebral I/R. METHODS: In this study, male Sprague-Dawley (SD) rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury were treated with EA at LI11 and ST36 for 30 min daily after MCAO/R for seven consecutive days. The neuroprotective effects of EA were measured by neurobehavioral evaluation, triphenyltetrazolium chloride staining, hematoxylin-eosin staining and transmission electron microscopy. Oxidative stress, inflammatory factors, neural apoptosis and microglial activation were examined by enzyme-linked immunosorbent assay, immunofluorescence and reverse transcriptase polymerase chain reaction. Western blotting was used to assess PPAR-γ-mediated signaling. RESULTS: We found that EA significantly alleviated cerebral I/R-induced infarct volume, decreased neurological scores and inhibited I/R-induced oxidative stress, inflammatory responses and microglial activation. EA also increased PPAR-γ protein expression. Furthermore, the protective effects of EA were reversed by injection of the PPAR-γ antagonist T0070907. CONCLUSION: EA attenuates cerebral I/R injury by regulating oxidative stress, neuronal death and neuroinflammation via stimulation of PPAR-γ.
Asunto(s)
Isquemia Encefálica , Electroacupuntura , Estrés Oxidativo , PPAR gamma , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , PPAR gamma/metabolismo , PPAR gamma/genética , Masculino , Daño por Reperfusión/terapia , Daño por Reperfusión/metabolismo , Daño por Reperfusión/inmunología , Ratas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Neuronas/metabolismo , Humanos , Enfermedades Neuroinflamatorias/terapia , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Muerte Celular , Modelos Animales de EnfermedadRESUMEN
The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.
Asunto(s)
Anticonvulsivantes/farmacología , Antioxidantes/farmacología , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Extractos Vegetales/farmacología , Stevia , Animales , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Apoptosis , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Epilepsia/inmunología , Epilepsia/metabolismo , Hipocampo/inmunología , Hipocampo/metabolismo , Masculino , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Pentilenotetrazol/farmacología , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
OBJECTIVE: Angelica (A.) sinensis is used as a traditional medical herb for the treatment of neurodegeneration, aging, and inflammation in Asia. A. sinensis optimal formula (AOF) is the best combination in A. sinensis that has been screened to rescue the cognitive ability in ß-amyloid peptide (Aß25-35)-treated Alzheimer's disease (AD) rats. The objective of this study was to investigate the effect of AOF on the learning and memory of AD rats as well as to explore the underlying mechanisms. METHODS: Male Wistar rats were infused with Aß25-35 for AD model induction or saline (negative control). Five groups of AD rats were fed on AOF at 20, 40, or 80 mL/kg every day, donepezil at 0.9 mg/kg every day (positive control), or an equal volume of water (AD model) intragastrically once a day for 4 weeks, while the negative control rats were fed on water. The Morris water maze test was used to evaluate the cognitive function of the rats. The Aß accumulation, cholinergic levels, and antioxidative ability were detected by ELISA. Additionally, the candidate mechanism was determined by gene sequencing and quantitative real-time polymerase chain reaction. RESULTS: The results showed that AOF administration significantly ameliorated Aß25-35-induced memory impairment. AOF decreased the levels of amyloid-ß precursor protein and Aß in the hippocampus, rescued the cholinergic levels, increased the activity of superoxide dismutase, and decreased the malondialdehyde level. In addition, AOF inhibited the expression of IL1b, Mpo, and Prkcg in the hippocampus. CONCLUSION: These experimental findings illustrate that AOF prevents the decrease in cognitive function and Aß deposits in Aß25-35-treated rats via modulating neuroinflammation and oxidative stress, thus highlighting a potential therapeutic avenue to promote the co-administration of formulas that act on different nodes to maximize beneficial effects and minimize negative side effects.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/farmacología , Angelica sinensis , Trastornos de la Memoria/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Nootrópicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Preparaciones de Plantas/farmacología , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/inmunología , Trastornos de la Memoria/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Nootrópicos/administración & dosificación , Preparaciones de Plantas/administración & dosificación , Ratas , Ratas WistarRESUMEN
Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance the cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural lead for the design and development of a novel neuroprotective drug.
Asunto(s)
Encéfalo/metabolismo , Genisteína/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Diseño de Fármacos , Humanos , Trastornos de la Memoria/metabolismo , Enfermedades Neuroinflamatorias/metabolismoRESUMEN
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease characterized by multifocal perivascular infiltration of immune cells in the central nervous system (CNS). Cordycepin (3'-deoxyadenosine), an adenosine analogue initially extracted from the fungus Cordyceps militarisa, is one of the candidates that has multiple actions. We investigated that cordycepin attenuated the activation of LPS-induced mouse bone marrow-derived dendritic cells (BMDCs) and human monocyte-derived dendritic cells (MoDCs) through the inhibition of the AKT, ERK, NFκB, and ROS pathways and impaired the migration of BMDCs through the downregulation of adhesion molecules and chemokine receptors in vitro. In experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with cordycepin decreased the expression of trafficking factors in the CNS, inhibited the secretion of inflammatory cytokines (IFN-γ, IL-6, TNF-α, and IL-17), and attenuated disease symptoms. A chemokine array indicated that cordycepin treatment reversed the high levels of CCL6, PARRES2, IL-16, CXCL10, and CCL12 in the brain and spinal cord of EAE mice, consistent with the RNA-seq data. Moreover, cordycepin suppressed the release of neuroinflammatory cytokines by activated microglial cells, macrophages, Th17 cells, Tc1 cells, and Th1 cells in vitro. Furthermore, cordycepin treatment exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that cordycepin treatment may not only prevent the occurrence of MS by inhibiting DC activation and migration but also potentially ameliorates the progression of MS by reducing neuroinflammation, which may provide insights into the development of new approaches for the treatment of MS.
Asunto(s)
Desoxiadenosinas/uso terapéutico , Encefalomielitis Autoinmune Experimental/prevención & control , Mediadores de Inflamación/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Animales , Línea Celular Transformada , Células Cultivadas , Desoxiadenosinas/farmacología , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/prevención & control , Células RAW 264.7 , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment. The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Ácidos Cafeicos/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Lactatos/uso terapéutico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Ácidos Cafeicos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Enfermedad Crónica , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Cristalinas/metabolismo , Glucosa/metabolismo , Humanos , Lactatos/farmacología , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Fármacos Neuroprotectores/farmacología , Ratas Wistar , Receptores de Dopamina D2/metabolismoRESUMEN
Chronic stress is a potential problem associated with anxiety, depression, and cognitive dysfunction. Bee pollen, a powerful antioxidant, has many therapeutic effects. In this study, we aimed to examine the effects of one of the Anatolian bee pollens on depression/anxiety. 24 male Sprague Dawley rats were divided into 3 groups as control, stress, and bee pollen + stress. Bee pollen (200 mg/kg/day) was given to rats exposed to physical stress for 10 days. Open field test (OFT) and forced swimming test (FST) were applied to monitor the behavioral changes of the rats. After behavioral tests, the rats were euthanized. Brain-derived neurotrophic factor (BDNF), interleukin 1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) levels were measured by ELISA to evaluate neurological and biochemical changes in rat hippocampal tissue. In addition, malondialdehyde (MDA) and glutathione (GSH) levels in the brain were evaluated. According to the behavioral test results, bee pollen reduced anxiety-like behavior but did not affect depression-like behavior. We also found that bee pollen suppressed neuroinflammation while reducing oxidative stress and lipid peroxidation in hippocampal tissues. Moreover, bee pollen significantly increased the level of BDNF in the hippocampus. In conclusion, bee pollen reduced oxidative damage and neuroinflammation caused by immobilization stress in rat brain tissue. Therefore, we suggest that bee pollen may be an effective natural compound in alleviating the negative effects caused by immobilization stress.
Asunto(s)
Abejas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Enfermedades Neuroinflamatorias/etiología , Polen , Animales , Antioxidantes/farmacología , Hipocampo/metabolismo , Masculino , Enfermedades Neuroinflamatorias/metabolismo , Ratas , Ratas Sprague-Dawley , Restricción Física/psicología , Estrés Psicológico/psicologíaRESUMEN
Photobiomodulation is a non-pharmacological tool widely used to reduce inflammation in many tissues. However, little is known about its effects on the inflammatory response in the aged brain. We conducted the study to examine anti-inflammatory effects of photobiomodulation in aging brains. We used aged rats (20 months old) with control (handled, laser off) or transcranial laser (660 nm wavelength, 100 mW power) treatments for 10 consecutive days and evaluated the level of inflammatory cytokines and chemokines, and the expression and activation of intracellular signaling proteins in the cerebral cortex and the hippocampus. Inflammatory analysis showed that aged rats submitted to transcranial laser treatment had increased levels of IL-1alpha and decreased levels of IL-5 in the cerebral cortex. In the hippocampus, the laser treatment increased the levels of IL-1alpha and decreased levels of IL-5, IL-18, and fractalkine. Regarding the intracellular signaling proteins, a reduction in the ERK and p38 expression and an increase in the STAT3 and ERK activation were observed in the cerebral cortex of aged rats from the laser group. In addition, the laser treatment increased the hippocampal expression of p70S6K, STAT3, and p38 of aged rats. Taken together, our data indicate that transcranial photobiomodulation can improve the inflammatory response and the activation of intracellular signaling proteins linked to vascular function and cell survival in the aged brain.
Asunto(s)
Envejecimiento/metabolismo , Supervivencia Celular/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Terapia por Luz de Baja Intensidad , Enfermedades Neuroinflamatorias/terapia , Animales , Encéfalo/metabolismo , Citocinas/metabolismo , Masculino , Enfermedades Neuroinflamatorias/metabolismo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Neurotoxic microglia and astrocytes begin to activate and participate in pathological processes after spinal cord injury (SCI), subsequently causing severe secondary damage and affecting tissue repair. We have previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM ameliorates neuroinflammation by modulating the activation of microglia and astrocytes after SCI. METHODS: Male Sprague-Dawley rats were randomly divided into three groups: a sham control group, an SCI + vehicle group and an SCI + PBM group. PBM was performed for two consecutive weeks after clip-compression SCI models were established. The activation of neurotoxic microglia and astrocytes, the level of tissue apoptosis, the number of motor neurons and the recovery of motor function were evaluated at different days post-injury (1, 3, 7, 14, and 28 days post-injury, dpi). Lipocalin 2 (Lcn2) and Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) signaling were regarded as potential targets by which PBM affected neurotoxic microglia and astrocytes. In in vitro experiments, primary microglia and astrocytes were irradiated with PBM and cotreated with cucurbitacin I (a JAK2-STAT3 pathway inhibitor), an adenovirus (shRNA-Lcn2) and recombinant Lcn2 protein. RESULTS: PBM promoted the recovery of motor function, inhibited the activation of neurotoxic microglia and astrocytes, alleviated neuroinflammation and tissue apoptosis, and increased the number of neurons retained after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also showed that Lcn2 and JAK2-STAT3 were mutually promoted and that PBM interfered with this interaction, inhibiting the activation of microglia and astrocytes. CONCLUSION: Lcn2/JAK2-STAT3 crosstalk is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be suppressed by PBM.
Asunto(s)
Astrocitos/efectos de la radiación , Terapia por Luz de Baja Intensidad , Microglía/efectos de la radiación , Recuperación de la Función/efectos de la radiación , Traumatismos de la Médula Espinal/patología , Animales , Astrocitos/metabolismo , Janus Quinasa 2/metabolismo , Janus Quinasa 2/efectos de la radiación , Lipocalina 2/metabolismo , Lipocalina 2/efectos de la radiación , Masculino , Microglía/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/efectos de la radiación , Transducción de Señal/efectos de la radiación , Traumatismos de la Médula Espinal/metabolismo , Regulación hacia ArribaRESUMEN
ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.
Asunto(s)
Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X3/metabolismo , Trastornos Somatosensoriales/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Potenciales de la Membrana/efectos de los fármacos , Ratones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ratas , Receptores Purinérgicos P2X3/genética , Trastornos Somatosensoriales/tratamiento farmacológico , Trastornos Somatosensoriales/etiologíaRESUMEN
Astragaloside IV (AS-IV) is an active component in Astragalus membranaceus with the potential to treat neurodegenerative diseases, especially Alzheimer's diseases (ADs). However, its mechanisms are still not known. Herein, we aimed to explore the systematic pharmacological mechanism of AS-IV for treating AD. Drug prediction, network pharmacology, and functional bioinformatics analyses were conducted. Molecular docking was applied to validate reliability of the interactions and binding affinities between AS-IV and related targets. Finally, experimental verification was carried out in AßO infusion produced AD-like phenotypes to investigate the molecular mechanisms. We found that AS-IV works through a multitarget synergistic mechanism, including inflammation, nervous system, cell proliferation, apoptosis, pyroptosis, calcium ion, and steroid. AS-IV highly interacted with PPARγ, caspase-1, GSK3Β, PSEN1, and TRPV1 after docking simulations. Meanwhile, PPARγ interacts with caspase-1, GSK3Β, PSEN1, and TRPV1. In vivo experiments showed that AßO infusion produced AD-like phenotypes in mice, including impairment of fear memory, neuronal loss, tau hyperphosphorylation, neuroinflammation, and synaptic deficits in the hippocampus. Especially, the expression of PPARγ, as well as BDNF, was also reduced in the hippocampus of AD-like mice. Conversely, AS-IV improved AßO infusion-induced memory impairment, inhibited neuronal loss and the phosphorylation of tau, and prevented the synaptic deficits. AS-IV prevented AßO infusion-induced reduction of PPARγ and BDNF. Moreover, the inhibition of PPARγ attenuated the effects of AS-IV on BDNF, neuroflammation, and pyroptosis in AD-like mice. Taken together, AS-IV could prevent AD-like phenotypes and reduce tau hyperphosphorylation, synaptic deficits, neuroinflammation, and pyroptosis, possibly via regulating PPARγ.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Astragalus propinquus/química , Medicamentos Herbarios Chinos/administración & dosificación , Enfermedades Neuroinflamatorias/prevención & control , Fenotipo , Fitoterapia/métodos , Saponinas/administración & dosificación , Triterpenos/administración & dosificación , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Péptidos beta-Amiloides/efectos adversos , Animales , Biología Computacional/métodos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular/métodos , Farmacología en Red/métodos , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/metabolismo , PPAR gamma/metabolismo , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/efectos adversos , Fosforilación/efectos de los fármacos , Piroptosis/efectos de los fármacos , Saponinas/metabolismo , Transducción de Señal/efectos de los fármacos , Máquina de Vectores de Soporte , Triterpenos/metabolismo , Proteínas tau/metabolismoRESUMEN
Isorhamnetin (ISO), a flavonoid compound isolated from sea-buckthorn (Hippophae rhamnoides L.) fruit, has anti-inflammatory effects. However, the effects of ISO on neuroinflammation and cognitive function are still unclear. The purpose of this study was to evaluate the protective effect of ISO on cognitive impairment in obese mice induced by a high-fat and high fructose diet (HFFD). It has been found that oral administration of ISO (0.03% w/w and 0.06% w/w) for 14 weeks significantly reduced the body weight, food intake, liver weight, liver lipid level, and serum lipid level of HFFD-fed mice. ISO can also significantly prevent HFFD-induced neuronal working, spatial, and long-term memory impairment. Notably, the ISO treatment activated the CREB/BDNF pathway and increased neurotrophic factors in the brains of mice. Furthermore, ISO inhibited HFFD-induced microglial overactivation and down-regulated inflammatory cytokines in both serum and the brain. It can also inhibit the expression of p-JNK, p-p38, and p-NFκB protein in the mouse brain. In conclusion, these results indicated that ISO mitigated HFFD-induced cognitive impairments by inhibiting the MAPK and NFκB signaling pathways, suggesting that ISO might be a plausible nutritional intervention for metabolic syndrome-related cognitive complications.
Asunto(s)
Disfunción Cognitiva/prevención & control , Dieta Alta en Grasa/efectos adversos , Azúcares de la Dieta/administración & dosificación , Suplementos Dietéticos , Enfermedades Neuroinflamatorias/prevención & control , Quercetina/análogos & derivados , Transducción de Señal , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Azúcares de la Dieta/efectos adversos , Fructosa/administración & dosificación , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Microglía/fisiología , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Quercetina/administración & dosificación , Aumento de PesoRESUMEN
The main mechanism of pyroptosis is Caspase-1-mediated GSDMD cleavage, and GSDMD is also the executive protein of pyroptosis. Our previous study has shown that mafenide can inhibit pyroptosis by inhibiting the GSDMD-Asp275 site to suppress cleavage. In this study, sulfonamide was used as the parent nucleus structure to synthesize sulfa-4 and sulfa-20. Screening of drug activity in the pyroptosis model of BV2 and iBMDM cell lines revealed the efficacy of five compounds were superior to mafenide, which exerted a better inhibitory effect on the occurrence of pyroptosis. For in vivo assay, Sulfa-4 and Sulfa-22 were intervened in the neuroinflammation APP/PS1 mice. As a result, the administration of Sulfa-4 and Sulfa-22 could significantly inhibit the activation of microglia, decrease the expression of inflammatory factors in the central nervous system and simultaneously suppress the production of p30-GSDMD as well as the expression of upstream NLRP3 inflammasome and Caspase-1 protein. Immunoprecipitation and Biotin-labelled assay confirmed the targeted binding relationship of Sulfa-4 and Sulfa-22 with GSDMD protein in the iBMDM model in vitro. In this study, we investigated a new type inhibitor of GSDMD cleavage, which exerted a good inhibitory effect on pyroptosis and provided new references for the development of inflammatory drugs in the future.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Antiinflamatorios/farmacología , Mafenida/farmacología , Enfermedades Neuroinflamatorias/etiología , Piroptosis/efectos de los fármacos , Animales , Antiinflamatorios/química , Biomarcadores , Línea Celular , Citocinas/metabolismo , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Mediadores de Inflamación , Mafenida/análogos & derivados , Mafenida/química , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Relación Estructura-ActividadRESUMEN
The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Animales , Axones/patología , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/metabolismo , Depresión/etiología , Depresión/prevención & control , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/psicología , Femenino , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estrés Oxidativo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Pramipexol/farmacología , Pramipexol/uso terapéutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Método Simple Ciego , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
Microglial activation and neuroinflammation induced by amyloid ß (Aß) play pivotal roles in Alzheimer's disease (AD) pathogenesis. Astragaloside IV (AS-IV) is one of the major active compounds of the traditional Chinese medicine Astmgali Radix. It has been reported that AS-IV could protect against Aß-induced neuroinflammation and cognitive impairment, but the underlying mechanisms need to be further clarified. In this study, the therapeutic effects of AS-IV were investigated in an oligomeric Aß (oAß) induced AD mice model. The effects of AS-IV on microglial activation, neuronal damage and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were further studied. Different doses of AS-IV were administered intragastrically once a day after intracerebroventricularly oAß injection. Results of behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test revealed that AS-IV administration could significantly ameliorate oAß-induced cognitive impairment in a dose dependent manner. Enzyme linked immunosorbent assay (ELISA) results showed that increased levels of reactive oxygen species (ROS), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in hippocampal tissues induced by oAß injection were remarkably inhibited after AS-IV treatment. OAß induced microglial activation and neuronal damage was significantly suppressed in AS-IV-treated mice brain, observed in immunohistochemistry results. Furthermore, oAß upregulated protein expression of NADPH oxidase subunits gp91phox, p47phox, p22phox and p67phox were remarkably reduced by AS-IV in Western blotting assay. These results revealed that AS-IV could ameliorate oAß-induced cognitive impairment, neuroinflammation and neuronal damage, which were possibly mediated by inhibition of microglial activation and down-regulation of NADPH oxidase protein expression. Our findings provide new insights of AS-IV for the treatment of neuroinflammation related diseases such as AD.
Asunto(s)
Enfermedad de Alzheimer , Planta del Astrágalo/química , Disfunción Cognitiva , Microglía/efectos de los fármacos , NADPH Oxidasas/metabolismo , Enfermedades Neuroinflamatorias , Saponinas/farmacología , Triterpenos/farmacología , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos adversos , Animales , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto , Ratones Endogámicos ICR , NADP , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Neuronas , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fitoterapia , Especies Reactivas de Oxígeno/metabolismo , Saponinas/uso terapéutico , Triterpenos/uso terapéuticoRESUMEN
Ischemic stroke (IS) caused by cerebral arterial occlusion is the leading cause of global morbidity and mortality. Cellular oxidative stress and inflammation play a vital role in the pathological process of neural damage in IS. It is necessary to develop functional food or drugs, which target neuroinflammation and oxidation mechanisms against IS. The molecule compound aloe-emodin (AE) is derived from aloe and rhubarb. However, the exact mechanism of the pharmacological action of AE on IS remains unclear. Here, for aiming to demonstrate the mechanism of AE, our study explored the middle cerebral occlusion reperfusion (MCAO/R) rats in vivo, oxygen and glucose deprivation reperfusion (OGD/R), and lipopolysaccharide (LPS)-stimulated cells in vitro. We found that AE significantly improved the infarct size and behavioral score of MCAO/R rats, decreased the expression of TNF-α, MDA, LDH, Caspase 3, and increased the expression of SOD, Bcl-2/Bax. Liquid chromatography-mass spectrometry (LC/MS) results showed that AE could penetrate the blood-brain barrier in the sham group and MCAO/R group. In vitro, AE significantly protected SH-SY5Y cells from the insult of OGD/R and reduced the production of inflammatory cytokines in BV2 cells stimulated by LPS. In vivo and in vitro, western blot analysis results showed that AE significantly increased the expression of PI3K, AKT and mTOR proteins. In addition, AE significantly decreased NF-κB protein expression in BV2 cells. The use of AKT-specific inhibitor MK-2206 2HCL to inhibit AKT expression can block the protective effect of AE on SH-SY5Y cells subjected to OGD/R insults. Overall, our study suggests that AE protected against cerebral ischemia-reperfusion injury probably via the PI3K/AKT/mTOR and NF-κB signaling pathways. Thus, these results indicated that AE could be a promising first-line therapy for preventing and treating ischemic stroke and can be used as functional food.
Asunto(s)
Aloe/química , Emodina/administración & dosificación , Accidente Cerebrovascular Isquémico/complicaciones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Humanos , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Oxandrolone (OXA) is an androgen and anabolic steroid (AAS) that is used to reverse weight loss associated with some medical conditions. One of the side effects of OXA is its potential to induce depressive symptoms. Growing evidence suggested that neuroinflammation and cytokines play crucial roles in sickness behavioral and associated mood disturbances. Previous studies showed that metformin attenuated neuroinflammation. This study investigated the potential protective role of metformin against OXA-induced depression-like behavior and neuroinflammation. Twenty- four Wistar male rats were randomly grouped into four groups: the control group (Control) received only vehicle; the oxandrolone group (OXA) received oxandrolone (0.28 mg/kg, i.p); the metformin group (MET) received metformin (100 mg/kg, i.p); and the oxandrolone / metformin group (OXA + MET) received both oxandrolone (0.28 mg/kg, i.p) and metformin (100 mg/kg, i.p). These treatments were administered for fourteen consecutive days. Behavioral tests to measure depression-like behavior were conducted before and after treatments. qRT-PCR was used to measure the relative expression of proinflammatory and anti-inflammatory cytokines in the hippocampus and hypothalamus. The results showed that oxandrolone induced depression-like behavior and dysregulated pro-/anti-inflammatory cytokines, while metformin attenuated these effects. These findings suggest that metformin is a potential treatment to reverse the depressive effects induced by oxandrolone that involve neuroinflammatory effects.