Changes in neuroinflammatory markers and microglial density in the hippocampus and prefrontal cortex of the C58/J mouse model of autism.

Autism spectrum disorder (ASD) is a diverse group of neurodevelopmental conditions with complex origins. Individuals with ASD present various neurobiological abnormalities, including an altered immune response in the central nervous system and other tissues. Animal models like the C58/J inbred mouse strain are used to study biological characteristics of ASD. This strain is considered an idiopathic autism model because of its demonstrated reduced social preference and repetitive behaviours. Notably, C58/J mice exhibit alterations in dendritic arbour complexity, density and dendritic spines maturation in the hippocampus and prefrontal cortex (PFC), but inflammatory-related changes have not been explored in these mice. In this study, we investigated proinflammatory markers in the hippocampus and PFC of adult male C58/J mice. We discovered elevated levels of interferon gamma (IFN-γ) and monocyte chemoattractant protein 1 (MCP-1) in the hippocampus, suggesting increased inflammation, alongside a reduction in the anti-inflammatory enzyme arginase 1 (ARG1). Conversely, the PFC displayed reduced levels of TNF-α and MCP-1. Microglial analysis revealed higher levels of transmembrane protein 119 (TMEM119) and increased microglial density in a region-specific manner of the autistic-like mice, particularly in the PFC and hippocampus. Additionally, an augmented expression of the fractalkine receptor CX3CR1 was observed in the hippocampus and PFC of C58/J mice. Microglial morphological analysis shows no evident changes in the hippocampus of mice with autistic-like behaviours versus wild-type strain. These region-specific changes can contribute to modulate processes like inflammation or synaptic pruning in the C58/J mouse model of idiopathic autism.

Possible Implications of Obesity-Primed Microglia that Could Contribute to Stroke-Associated Damage.

Microglia, the resident macrophages of the central nervous system, are essential players during physiological and pathological processes. Although they participate in synaptic pruning and maintenance of neuronal circuits, microglia are mainly studied by their activity modulating inflammatory environment and adapting their phenotype and mechanisms to insults detected in the brain parenchyma. Changes in microglial phenotypes are reflected in their morphology, membrane markers, and secreted substances, stimulating neighbor glia and leading their responses to control stimuli. Understanding how microglia react in various microenvironments, such as chronic inflammation, made it possible to establish therapeutic windows and identify synergic interactions with acute damage events like stroke. Obesity is a low-grade chronic inflammatory state that gradually affects the central nervous system, promoting neuroinflammation development. Obese patients have the worst prognosis when they suffer a cerebral infarction due to basal neuroinflammation, then obesity-induced neuroinflammation could promote the priming of microglial cells and favor its neurotoxic response, potentially worsening patients' prognosis. This review discusses the main microglia findings in the obesity context during the course and resolution of cerebral infarction, involving the temporality of the phenotype changes and balance of pro- and anti-inflammatory responses, which is lost in the swollen brain of an obese subject. Obesity enhances proinflammatory responses during a stroke. Obesity-induced systemic inflammation promotes microglial M1 polarization and priming, which enhances stroke-associated damage, increasing M1 and decreasing M2 responses.

The Role of Glia in Addiction: Dopamine as a Modulator of Glial Responses in Addiction.

Addiction is a chronic and potentially deadly disease considered a global health problem. Nevertheless, there is still no ideal treatment for its management. The alterations in the reward system are the most known pathophysiological mechanisms. Dopamine is the pivotal neurotransmitter involved in neuronal drug reward mechanisms and its neuronal mechanisms have been intensely investigated in recent years. However, neuroglial interactions and their relation to drug addiction development and maintenance of drug addiction have been understudied. Many reports have found that most neuroglial cells express dopamine receptors and that dopamine activity may induce neuroimmunomodulatory effects. Furthermore, current research has also shown that pro- and anti-inflammatory molecules modulate dopaminergic neuron activity. Thus, studying the immune mechanisms of dopamine associated with drug abuse is vital in researching new pathophysiological mechanisms and new therapeutic targets for addiction management.

Differences in Diurnal Variation of Immune Responses in Microglia and Macrophages: Review and Perspectives.

Biological rhythms, especially those that last close to 24 h, better known as circadian rhythms, are highly regulated phenomena, maintained throughout evolution in various organisms which allow organisms to predict, prepare for, and adapt to environmental changes. One of these phenomena that exhibit biological rhythms is the immune response to external agents. Immune cells (neutrophils, lymphocytes, macrophages, among others), as well as their mediators such as cytokines and chemokines, undergo variations in tissue and blood concentrations during the day. These rhythms are still being elucidated in microglia, the resident macrophages of the central nervous system, but since these cells share a common origin with peripheral macrophages, they are expected to behave similarly. In this review, we will discuss the possible differences in the responses between peripheral macrophages and microglia, their relationship with the circadian clock, and whether these rhythms can influence therapeutic choices.

Correction to: Differences in Diurnal Variation of Immune Responses in Microglia and Macrophages: Review and Perspectives.

The original version of this article unfortunately contained an error in the author group. The given name and family name was interchanged for the two co-authors. The author name should be Anahí Chavarría and Luz Navarro instead it was published incorrectly as Chavarría Anahí and Navarro Luz. The original article has been corrected.

Silybin restores glucose uptake after tumour necrosis factor-alpha and lipopolysaccharide stimulation in 3T3-L1 adipocytes.

Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study evaluated the effect of silybin, the main bioactive component of silymarin, which has anti-inflammatory properties, on TNFα levels and its impact on glucose uptake in the adipocyte cell line 3T3-L1 challenged with two different inflammatory stimuli, TNFα or lipopolysaccharide (LPS). Silybin's pre-treatment effect was evaluated in adipocytes pre-incubated with silybin (30 or 80 µM) before challenging with the inflammatory stimuli (TNFα or LPS). For the post-treatment effect, the adipocytes were first challenged with the inflammatory stimuli and then post-treated with silybin. After treatments, TNFα production, glucose uptake, and GLUT4 protein expression were determined. Both inflammatory stimuli increased TNFα secretion, diminished GLUT4 expression, and significantly decreased glucose uptake. Silybin 30 µM only reduced TNFα secretion after the LPS challenge. Silybin 80 µM as post-treatment or pre-treatment decreased TNFα levels, improving glucose uptake. However, glucose uptake enhancement induced by silybin did not depend on GLUT4 protein expression. These results show that silybin importantly reduced TNFα levels and upregulates glucose uptake, independently of GLUT4 protein expression.

Clavulanic Acid and its Potential Therapeutic Effects on the Central Nervous System.

Clavulanic acid (CLAV) is a non-antibiotic ß-lactam that has been used since the late 1970s as a ß-lactamase inhibitor in combination with amoxicillin, another ß-lactam with antibiotic activity. Its long-observed adverse reaction profile allows it to say that CLAV is a well-tolerated drug with mainly mild adverse reactions. Interestingly, in 2005, it was discovered that ß-lactams enhance the astrocytic expression of GLT-1, a glutamate transporter essential for maintaining synaptic glutamate homeostasis involved in several pathologies of the central nervous system (CNS). This finding, along with a favorable pharmacokinetic profile, prompted the appearance of several studies that intended to evaluate the effect of CLAV in preclinical disease models. Studies have revealed that CLAV can increase GLT-1 expression in the nucleus accumbens (NAcc), medial prefrontal cortex (PFC), and spinal cord of rodents, to affect glutamate and dopaminergic neurotransmission, and exert an anti-inflammatory effect by modulating the levels of the cytokines TNF-α and interleukin 10 (IL-10). CLAV has been tested with positive results in preclinical models of epilepsy, addiction, stroke, neuropathic and inflammatory pain, dementia, Parkinson's disease, and sexual and anxiety behavior. These properties make CLAV a potential therapeutic drug if repurposed. Therefore, this review aims to gather information on CLAV's effect on preclinical neurological disease models and to give some perspectives on its potential therapeutic use in some diseases of the CNS.

Oral Administration of Silybin Protects Against MPTP-Induced Neurotoxicity by Reducing Pro-inflammatory Cytokines and Preserving BDNF Levels in Mice.

Parkinson's disease (PD) is the second most frequent neurodegenerative disease associated with motor dysfunction secondary to the loss of dopaminergic neurons in the nigrostriatal axis. Actual therapy consists mainly of levodopa; however, its long-term use promotes secondary effects. Consequently, finding new therapeutic alternatives, such as neuroprotective molecules, is necessary. Among these alternatives is silybin (Sb), the major bioactive flavonolignan in silymarin. Both exert neuroprotective effects, preserving dopamine levels and dopaminergic neurons when administered in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model, being probably Sb the potential therapeutic molecule behind this effect. To elucidate the role of Sb in the PD model, we determined the dose-dependent conservation of striatal dopamine content following Sb oral administration. Then, we evaluated motor deficit tests using the best dopamine conservative dose of Sb and determined a cytokine-dependent inflammatory profile status, malondialdehyde as an oxidative stress product, and neurotrophic factors content in the MPTP-induced mouse PD model. Our results show that oral Sb at 100 mg/kg dose conserved about 60% dopamine levels. Also, Sb improved motor deficits, preserved neurotrophic factors content and mitochondrial function, reduced lipid peroxidation, diminished proinflammatory cytokines to basal levels, enhanced fractalkine production in the striatum and substantia nigra, and increased IL-10 and IL-4 levels in the substantia nigra in the MPTP mice. Thus, oral Sb may be a potential pharmacological PD treatment alternative.

Chronic consumption of a hypercaloric diet increases neuroinflammation and brain senescence, promoting cognitive decline in middle-aged female Wistar rats.

Being overweight and obesity are world health problems, with a higher prevalence in women, defined as abnormal or excessive fat accumulation that increases the risk of chronic diseases. Excess energy leads to adipose expansion, generating hypertrophic adipocytes that produce various pro-inflammatory molecules. These molecules cause chronic low-intensity inflammation, affecting the organism's functioning and the central nervous system (CNS), inducing neuroinflammation. The neuroinflammatory response during obesity occurs in different structures of the CNS involved in memory and learning, such as the cortex and the hippocampus. Here we analyzed how obesity-related peripheral inflammation can affect CNS physiology, generating neuroinflammation and promoting cellular senescence establishment. Since some studies have shown an increase in senescent cells during aging, obesity, and neurodegenerative diseases, we proposed that cellular senescence participation may contribute to the cognitive decline in an obesity model of middle-aged female Wistar rats. The inflammatory state of 6 and 13 months-old female Wistar rats fed with a hypercaloric diet was measured in serum and CNS (cortex and hippocampus). Memory was evaluated using the novel object recognition (NOR) test; the presence of senescent markers was also determined. Our data suggest that the systemic inflammation generated by obesity induces a neuroinflammatory state in regions involved in learning and memory, with an increase in senescent markers, thus proposing senescence as a potential participant in the negative consequences of obesity in cognition.

Central nervous system: a modified immune surveillance circuit?

Immune surveillance in the central nervous system (CNS) was considered impossible because: (i) the brain parenchyma is separated from the blood circulation by the blood-brain barrier (BBB); (ii) the brain lacks lymphatic drainage and (iii) the brain displays low major histocompatibility complex class II (MHCII) expression. In this context, the BBB prevents entry of immune molecules and effector cells to the CNS. The absence of lymphatic vessels avoids CNS antigens from reaching the lymph nodes for lymphocyte presentation and activation. Finally, the low MHCII expression hinders effective antigen presentation and re-activation of T cells for a competent immune response. All these factors limit the effectiveness of the afferent and efferent arms necessary to carry out immune surveillance. Nevertheless, recent evidence supports that CNS is monitored by the immune system through a modified surveillance circuit; this work reviews these findings.

Neurocysticercosis: local and systemic immune-inflammatory features related to severity.

Neurocysticercosis (NC) is caused by the establishment of Taenia solium cysticerci in the central nervous system. Previous studies have established that neuroinflammation plays a key role in the severity of the disease. However, the relationship between peripheral and local immune response remains inconclusive. This work studies the peripheral and local immune-inflammatory features and their relationships, toward the identification of potential peripheral immunologic features related to severity. A panel of cytokines was measured in paired cerebrospinal fluid (CSF) and in the supernatant of antigen-specific stimulated peripheral blood mononuclear cells samples (SN) in a total of 31 untreated inflammatory and non-inflammatory NC patients. Increased clinical and radiologic severity was associated with an increased cerebrospinal fluid cell count. A peripheral proliferative depression that negatively correlates with CSF cellularity and TNFα and that positively correlates with SN IL5 was observed in severe NC patients. These results provide evidences to support the systemic proliferative response as a biomarker to monitor the level of neuroinflammation, of possible value in the patients' follow-up during treatment.

The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit.

Overweight and obesity are now considered a worldwide pandemic and a growing public health problem with severe economic and social consequences. Adipose tissue is an organ with neuroimmune-endocrine functions, which participates in homeostasis. So, adipocyte hypertrophy and hyperplasia induce a state of chronic inflammation that causes changes in the brain and induce neuroinflammation. Studies with obese animal models and obese patients have shown a relationship between diet and cognitive decline, especially working memory and learning deficiencies. Here we analyze how obesity-related peripheral inflammation can affect central nervous system physiology, generating neuroinflammation. Given that the blood-brain barrier is an interface between the periphery and the central nervous system, its altered physiology in obesity may mediate the consequences on various cognitive processes. Finally, several interventions, and the use of natural compounds and exercise to prevent the adverse effects of obesity in the brain are also discussed.

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson's Disease Model.

Systemic inflammation is a crucial factor for microglial activation and neuroinflammation in neurodegeneration. This work is aimed at assessing whether previous exposure to systemic inflammation potentiates neurotoxic damage by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and how chronic systemic inflammation participates in the physiopathological mechanisms of Parkinson's disease. Two different models of systemic inflammation were employed to explore this hypothesis: a single administration of lipopolysaccharide (sLPS; 5 mg/kg) and chronic exposure to low doses (mLPS; 100 µg/kg twice a week for three months). After three months, both groups were challenged with MPTP. With the sLPS administration, Iba1 staining increased in the striatum and substantia nigra, and the cell viability lowered in the striatum of these mice. mLPS alone had more impact on the proinflammatory profile of the brain, steadily increasing TNFα levels, activating microglia, reducing BDNF, cell viability, and dopamine levels, leading to a damage profile similar to the MPTP model per se. Interestingly, mLPS increased MAO-B activity possibly conferring susceptibility to MPTP damage. mLPS, along with MPTP administration, exacerbated the neurotoxic effect. This effect seemed to be coordinated by microglia since minocycline administration prevented brain TNFα increase. Coadministration of sLPS with MPTP only facilitated damage induced by MPTP without significant change in the inflammatory profile. These results indicate that chronic systemic inflammation increased susceptibility to MPTP toxic effect and is an adequate model for studying the impact of systemic inflammation in Parkinson's disease.

Intranasal Dexamethasone Reduces Mortality and Brain Damage in a Mouse Experimental Ischemic Stroke Model.

Neuroinflammation triggered by the expression of damaged-associated molecular patterns released from dying cells plays a critical role in the pathogenesis of ischemic stroke. However, the benefits from the control of neuroinflammation in the clinical outcome have not been established. In this study, the effectiveness of intranasal, a highly efficient route to reach the central nervous system, and intraperitoneal dexamethasone administration in the treatment of neuroinflammation was evaluated in a 60-min middle cerebral artery occlusion (MCAO) model in C57BL/6 male mice. We performed a side-by-side comparison using intranasal versus intraperitoneal dexamethasone, a timecourse including immediate (0 h) or 4 or 12 h poststroke intranasal administration, as well as 4 intranasal doses of dexamethasone beginning 12 h after the MCAO versus a single dose at 12 h to identify the most effective conditions to treat neuroinflammation in MCAO mice. The best results were obtained 12 h after MCAO and when mice received a single dose of dexamethasone (0.25 mg/kg) intranasally. This treatment significantly reduced mortality, neurological deficits, infarct volume size, blood-brain barrier permeability in the somatosensory cortex, inflammatory cell infiltration, and glial activation. Our results demonstrate that a single low dose of intranasal dexamethasone has neuroprotective therapeutic effects in the MCAO model, showing a better clinical outcome than the intraperitoneal administration. Based on these results, we propose a new therapeutic approach for the treatment of the damage process that accompanies ischemic stroke.

S-Allylcysteine Protects Against Excitotoxic Damage in Rat Cortical Slices Via Reduction of Oxidative Damage, Activation of Nrf2/ARE Binding, and BDNF Preservation.

Neuroprotective approaches comprising different mechanisms to counteract the noxious effects of excitotoxicity and oxidative stress need validation and detailed characterization. Although S-allylcysteine (SAC) is a natural compound exhibiting a broad spectrum of protective effects characterized by antioxidant, anti-inflammatory, and neuromodulatory actions, the mechanisms underlying its protective role on neuronal cell damage triggered by early excitotoxic insults remain elusive. In this study, we evaluated if the preconditioning or the post-treatment of isolated rat cortical slices with SAC (100 µM) can ameliorate the toxic effects induced by the excitotoxic metabolite quinolinic acid (QUIN, 100 µM), and whether this protective response involves the early display of specific antioxidant and neuroprotective signals. For this purpose, cell viability/mitochondrial reductive capacity, lipid peroxidation, levels of reduced and oxidized glutathione (GSH and GSSG, respectively), the rate of cell damage, the NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) binding activity, heme oxygenase 1 (HO-1) regulation, extracellular signal-regulated kinase (ERK1/2) phosphorylation, and the levels of tumor necrosis factor-alpha (TNF-α) and the neurotrophin brain-derived neurotrophic factor (BDNF) were all estimated in tissue slices exposed to SAC and/or QUIN. The incubation of slices with QUIN augmented all toxic endpoints, whereas the addition of SAC prevented and/or recovered all toxic effects of QUIN, exhibiting better results when administered 60 min before the toxin and demonstrating protective and antioxidant properties. The early stimulation of Nrf2/ARE binding activity, the upregulation of HO-1, the ERK1/2 phosphorylation and the preservation of BDNF tissue levels by SAC demonstrate that this molecule displays a wide range of early protective signals by triggering orchestrated antioxidant responses and neuroprotective strategies. The relevance of the characterization of these mechanisms lies in the confirmation that the protective potential exerted by SAC begins at the early stages of excitotoxicity and neurodegeneration and supports the design of integral prophylactic/therapeutic strategies to reduce the deleterious effects observed in neurodegenerative disorders with inherent excitotoxic events.

Pediatric ependymoma: GNAO1, ASAH1, IMMT and IPO7 protein expression and 5-year prognosis correlation.

OBJECTIVE: The aim of this work was to evaluate a pediatric ependymoma protein expression that may be useful as a molecular biomarker candidate for prognosis, correlated with clinical features such as age, gender, histopathological grade, ependymal tumor recurrence and patient survival. PATIENTS AND METHODS: Immunohistochemistry assays were performed for GNAO1, ASAH1, IMMT, IPO7, Cyclin D1, P53 and Ki-67 proteins. Kaplan-Meier and Cox analysis were performed for age, gender, histopathological grade, relapse and survival correlation. RESULTS: We found that three proteins correlate with histopathological grade and relapse; two proteins correlate with survival; one protein does not correlate with any clinical feature. CONCLUSION: Our results suggest that, out of the proteins analyzed, five may be considered suitable prognostic biomarkers and one may be considered a predictive biomarker for response to treatment of pediatric ependymoma.

Oral Silica Nanoparticles Lack of Neurotoxic Effects in a Parkinson's Disease Model: A Possible Nanocarrier?

Silica nanoparticles (SiO2-NP) are an option as drug carriers due to their biodegradability, biocompatibility, and capacity to bind themselves to other compounds. However, until now, the effect of these particles on the brain when neurodegeneration occurs is unknown. Hence, this work focused on the in vivo evaluation of the neurotoxic effects of SiO2-NP when oxidative and inflammation are present during the development of Parkinson's disease. To determine whether SiO2-NP may act as a non-neurotoxic carrier we evaluated if the intragastric administration (ig) of SiO2-NP of 150 nm (25, 50 and 100 mg/kg administered for five consecutive days) increased neuronal damage induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. SiO2-NP administration did not further decrease cell viability assessed by MTT reduction, nor increased lipid peroxidation measured by TBARS or TNF α levels in the striatum and the substantia nigra in the MPTP model. Furthermore, we observed no additional reduction in striatal dopamine levels. The present results suggest that SiO2-NP of 150 nm are suitable nanocarrier for Parkinson's disease drugs without generating any additional damage.

The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation.

The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system. Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders. In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats. URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 µL intrastriatal, 240 nmol/µL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1). Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.

A Malva parviflora´s fraction prevents the deleterious effects resulting from neuroinflammation.

Neuroinflammation, a centralized immune response, is a physiological process by which the organism attempts to remove an injurious stimulus in the central nervous system. Nonetheless, it is known that chronic inflammatory processes play an important role in the onset and progression of neurodegenerative disorders, such as Alzheimer´s disease (AD). Based on this, new strategies to treat AD have been proposed. Among them, the use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of this disease. Unfortunately, the prolonged use of NSAIDs results in adverse secondary effects. In this context, plants secondary metabolites have become of great interest. Particularly, our group has demonstrated that the hydroalcoholic extract of Malva parviflora (MpHA) has anti-inflammatory effect and is capable of improving the cognitive deficit present in an AD model. To further characterize the Malva parviflora compounds with anti-inflammatory properties, here we generated a fraction from a dichloromethane extract, which constitutes a less complex mix of compounds than the MpHA. This approach allowed us to isolate a fraction (MpF10) with anti-inflammatory activity, able to ameliorate the spatial learning and memory impairment, and to reduce both astrogliosis as well as IL-1ß and TNF production in a murine model of LPS-mediated neuroinflammation. Among the identified compounds in the MpF10, we found daucosterol (MpDau), which prevented LPS-induced neuroinflammation. Interestingly, MpF10 and MpDau inhibit NFκB activity in macrophages exposed to LPS. Therefore, we propose that the compounds present in the MpF10 represent an alternative to treat neuroinflammation, an important process developed during neurodegenerative diseases such as AD.

Redox Signaling, Neuroinflammation, and Neurodegeneration.

SIGNIFICANCE: Production of pro-inflammatory and anti-inflammatory cytokines is part of the defense system that mostly microglia and macrophages display to induce normal signaling to counteract the deleterious actions of invading pathogens in the brain. Also, redox activity in the central nervous system (CNS) constitutes an integral part of the metabolic processes needed by cells to exert their normal molecular and biochemical functions. Under normal conditions, the formation of reactive oxygen and nitrogen species, and the following oxidative activity encounter a healthy balance with immunological responses to preserve cell functions in the brain. However, under different pathological conditions, inflammatory responses recruit pro-oxidant signals and vice versa. The aim of this article is to review the basic concepts about the triggering of inflammatory and oxidative responses in the CNS. Recent Advances: Diverse concurrent toxic pathways are described to provide a solid mechanistic scope for considering intervention at the experimental and clinical levels that are aimed at diminishing the harmful actions of these two contributing factors to nerve cell damage. Critical Issues and Future Directions: The main conclusion supports the existence of a narrow cross-talk between pro-inflammatory and oxidative signals that can lead to neuronal damage and subsequent neurodegeneration. Further investigation about critical pathways crosslinking oxidative stress and inflammation will strength our knowlegde on this topic. Antioxid. Redox Signal. 28, 1626-1651.