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. Graphical Abstract 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.

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.

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-1β 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.

Sleep loss promotes a chronic low-grade inflammatory status with increased levels of inflammatory cytokines. Sleep loss also induces low-grade neuroinflammation characterized by glial reactivity and blood–brain barrier (BBB) dysfunction, as evidenced by BBB hyperpermeability and tight junction disassembly. Additionally, it raises molecules related to the senescence-associated secretory phenotype (SASP) in aged subjects, suggesting an increase in senescent cells. Here, we assessed the impact of sleep restriction on cellular senescence, neuroinflammation, and BBB function in the cerebral cortex and hippocampus of young male C57BL/6 mice. Sleep restriction induced a progressive increase in BBB permeability after 3, 5, and 10 days, along with a higher expression of the astroglial marker, the glial fibrillary acidic protein (GFAP), and the expression of the C3 complement component. The pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) increased in a region-dependent form. Furthermore, the progressive increase of the senescence markers β-galactosidase and p21 observed in both brain regions was accompanied by a neurotoxic astroglial response. Our data suggest that sleep restriction promotes cellular senescence in the cerebral cortex and hippocampus of young mice. Graphical Abstract

La obesidad es considerada actualmente como un problema de salud pública global y se caracteriza por la hipertrofia e hiperplasia del tejido adiposo debido a la ingesta hipercalórica y la falta de actividad física, desarrollando disfunción metabólica, inflamación sistémica crónica de bajo grado y gradualmente neuroinflamación hipotalámica. El tejido adiposo actúa como un órgano endocrino secretando adipocinas y citocinas alrededor de los órganos periféricos, actuando como regulador del metabolismo, sin embargo, la presencia de niveles elevados de ácidos grasos libres y de moléculas inflamatorias derivadas de los adipocitos, pueden alterar la respuesta inmunitaria sistémica, generando inflamación crónica, comprometiendo la integridad de la barrera hemato-encefálica y estimulando la respuesta de la glía, especialmente en regiones específicas del hipotálamo, centro de regulación de la homeostasis energética. Las células gliales hipotalámicas son importantes en la transmisión de señales inflamatorias relacionadas con la dieta y pueden modular la actividad neuronal, así como responder a las señales inmunológicas periféricas e iniciar la inflamación local y gliosis. Esta revisión se enfoca en la descripción general de la disfunción metabólica asociada a la obesidad y su participación en la alteración de la regulación hipotalámica, provocando neuroinflamación y modificaciones en la conducta alimentaria.