Focal mu-opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain.

Microglia participates in the modulation of pain signaling. The activation of microglia is suggested to play an important role in affective disorders that are related to a dysfunction of the mesocorticolimbic system (MCLS) and are commonly associated with chronic pain. Moreover, there is evidence that mu-opioid receptors (MORs), expressed in the MCLS, are involved in neuroinflammatory events, although the way by which they do it remains to be elucidated. In this study, we propose that MOR pharmacological activation within the MCLS activates and triggers the local release of proinflammatory cytokines and this pattern of activation is impacted by the presence of systemic inflammatory pain. To test this hypothesis, we used in vivo microdialysis coupled with flow cytometry to measure cytokines release in the nucleus accumbens and immunofluorescence of IBA1 in areas of the MCLS on a rat model of inflammatory pain. Interestingly, the treatment with DAMGO, a MOR agonist locally in the nucleus accumbens, triggered the release of the IL1α, IL1ß, and IL6 proinflammatory cytokines. Furthermore, MOR pharmacological activation in the ventral tegmental area (VTA) modified the levels of IBA1-positive cells in the VTA, prefrontal cortex, the nucleus accumbens and the amygdala in a dose-dependent way, without impacting mechanical nociception. Additionally, MOR blockade in the VTA prevents DAMGO-induced effects. Finally, we observed that systemic inflammatory pain altered the IBA1 immunostaining derived from MOR activation in the MSCLS. Altogether, our results indicate that the microglia-MOR relationship could be pivotal to unravel some inflammatory pain-induced comorbidities related to MCLS dysfunction.

Graphene-collagen cryogel controls neuroinflammation and fosters accelerated axonal regeneration in spinal cord injury.

Spinal cord injury (SCI) is a devastating condition resulting in loss of motor function. The pathology of SCI is multifaceted and involves a cascade of events, including neuroinflammation and neuronal degeneration at the epicenter, limiting repair process. We developed a supermacroporous, mechanically elastic, electro-conductive, graphene crosslinked collagen (Gr-Col) cryogels for the regeneration of the spinal cord post-injury. The effects of graphene in controlling astrocytes reactivity and microglia polarization are evaluated in spinal cord slice organotypic culture and rat spinal cord lateral hemisection model of SCI. In our work, the application of external electric stimulus results in the enhanced expression of neuronal markers in an organotypic culture. The implantation of Gr-Col cryogels in rat thoracic T9-T11 hemisection model demonstrates an improved functional recovery within 14 days post-injury (DPI), promoted myelination, and decreases the lesion volume at the injury site. Decrease in the expression of STAT3 in the implanted Gr-Col cryogels may be responsible for the decrease in astrocytes reactivity. Microglia cells within the implanted cryogels shows higher anti-inflammatory phenotype (M2) than inflammatory (M1) phenotype. The higher expression of mature axonal markers like ß-tubulin III, GAP43, doublecortin, and neurofilament 200 in the implanted Gr-Col cryogel confirms the axonal regeneration after 28 DPI. Gr-Col cryogels also modulate the production of ECM matrix, favouring the axonal regeneration. This study shows that Gr-Col cryogels decreases neuroinflammation and accelerate axonal regeneration.

Research progress on the role and regulatory mechanism of pathogenic Th17 cells in neuroinflammation.

Neuroinflammation is a complex immune response in the central nervous system against various factors such as injury, infection and toxins which interfere with homeostasis, involving a variety of immune cells lingering in the central nervous system. Persistent neuroinflammation is a common denominator of the etiology and course of all neurological diseases, including neurodevelopmental, neurodegenerative and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and depression. Th17 cells, known as an important subtpye of CD4 + T cells, mediate immune responses against extracellular bacteria and fungi in steady-state and maintain the defense function of the intestinal mucosal barrier. However, when the cytokine microenvironment in vivo undergoes inflammatory changes, Th17 cells can transform into a highly pro-inflammatory pathogenic phenotype, break through the blood-brain barrier and recruit more inflammatory cells to participate in neuroinflammation, ultimately leading to neurodegeneration. In this review, we summarize the differentiation regulation of pathogenic Th17 cells and their roles in neuroinflammation, which is informative for understanding the interactions between immune system and nervous system.

Inflammation at the crossroads of COVID-19, cognitive deficits and depression.

Acute neurological alterations have been associated with SARS-CoV-2 infection. Additionally, it is becoming clear that coronavirus disease 2019 (COVID-19) survivors may experience long-term neurological abnormalities, including cognitive deficits and mood alterations. The mechanisms underlying acute and long-term impacts of COVID-19 in the brain are being actively investigated. Due to the heterogeneous manifestations of neurological outcomes, it is possible that different mechanisms operate following SARS-CoV-2 infection, which may include direct brain infection by SARS-CoV-2, mechanisms resulting from hyperinflammatory systemic disease, or a combination of both. Inflammation is a core feature of COVID-19, and both central and systemic inflammation are known to lead to acute and persistent neurological alterations in other diseases. Here, we review evidence indicating that COVID-19 is associated with neuroinflammation, along with blood-brain barrier dysfunction. Similar neuroinflammatory signatures have been associated with Alzheimer's disease and major depressive disorder. Current evidence demonstrates that patients with pre-existing cognitive and neuropsychiatric deficits show worse outcomes upon infection by SARS-CoV-2 and, conversely, COVID-19 survivors may be at increased risk of developing dementia and mood disorders. Considering the high prevalence of COVID-19 patients that recovered from infection in the world and the alarming projections for the prevalence of dementia and depression, investigation of possible molecular similarities between those diseases may shed light on mechanisms leading to long-term neurological abnormalities in COVID-19 survivors.

Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression.

Depression is the most prevalent and debilitating mental disorder that affects a substantial number of people globally, hindering all aspects of their lives and leading to a high number of suicides each year. Despite the availability of an array of antidepressant medications, taking these medications does not relieve depressive symptoms in a considerable number of patients, implying that an incomplete understanding of the pathomechanisms involved in the development of depression. Besides that, a subset of those non-responsive patients exhibits an increased systemic and central inflammatory response, which has collectively led to the evolvement of the inflammatory theory of depression. Indeed, peripherally generated inflammatory mediators, as well as insults within the brain, can activate the brain's resident immune cells, resulting in a neuroinflammatory response that interferes with the multitude of neurobiological domains implicated in the pathogenesis of depression. Polyphenols, a group of plant-derived bioactive molecules, have been shown to exert neuroprotective functions on the brain by influencing an array of neuropathological mechanisms, including neuroinflammation. From these perspectives, this review mechanistically provides an overview of the neuropathological roles of sustained neuroinflammatory response in the development of depression and elucidates the therapeutic potential of flavonoid and nonflavonoid polyphenols in modulating inflammatory mediators and signaling cascades as well as promoting other neurophysiological and neuroprotective functions underlying inflammation-associated depressive symptoms. Therefore, given their significant anti-neuroinflammatory effects, polyphenols could be a promising and effective adjunctive therapy for the treatment of neuropsychiatric symptoms associated with inflammation-related depression.

IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation.

During inflammation, Ly6Chi monocytes are rapidly mobilized from the bone marrow (BM) and are recruited into inflamed tissues, where they undergo monocyte-to-phagocyte transition (MTPT). The in vivo developmental trajectories of the MTPT and the contribution of individual cytokines to this process remain unclear. Here, we used a murine model of neuroinflammation to investigate how granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFNγ), two type 1 cytokines, controlled MTPT. Using genetic fate mapping, gene targeting and high-dimensional single-cell multiomics analyses, we found that IFNγ was essential for the gradual acquisition of a mature inflammatory phagocyte phenotype in Ly6Chi monocytes, while GM-CSF was required to license interleukin-1ß (IL-1ß) production, phagocytosis and oxidative burst. These results suggest that the proinflammatory cytokine environment guided MTPT trajectories in the inflamed central nervous system (CNS) and indicated that GM-CSF was the most prominent target for the disarming of monocyte progenies during neuroinflammation.

Omarigliptin/galangin combination mitigates lipopolysaccharide-induced neuroinflammation in rats: Involvement of glucagon-like peptide-1, toll-like receptor-4, apoptosis and Akt/GSK-3ß signaling.

AIMS: The objectives of this work were to assess the possibility of administration of omarigliptin and/or galangin to combat lipopolysaccharide (LPS)-induced neuroinflammation in rats and to explore the possible mechanisms that might contribute to their actions. MATERIALS AND METHODS: In a rat model of LPS-induced neuroinflammation, the changes in the behavioral tests, biochemical parameters, and the histopathological picture were assessed. KEY FINDINGS: Administration of either omarigliptin or galangin to LPS-injected rats was able to significantly improve the behavioral changes with restoration of the oxidant/antioxidant balance, decrement of toll-like receptor-4 levels, and amelioration of the neuroinflammation associated with inhibition of apoptosis and restoration of glucagon-like peptide-1 levels in the cerebral tissues. In addition, omarigliptin and/or galangin significantly reduced the levels of phospho-Akt and glycogen synthase kinase 3 beta (GSK-3ß) and significantly increased the expression of beclin-1 in the cerebral tissues compared versus the group treated with LPS alone. As a result, these changes were positively reflected on the histopathological and the electron microscopic picture of the cerebral tissues. These beneficial effects were maximally evidenced in rats treated with omarigliptin/galangin combination relative to the use of either omarigliptin or galangin alone. SIGNIFICANCE: Omarigliptin/galangin combination might be proposed as a promising therapeutic line for mitigation of the pathophysiologic events of LPS-induced neuroinflammation.

Targeting neuroinflammation by intranasal delivery of nanoparticles in neurological diseases: a comprehensive review.

Neuroinflammation (NIF) plays an essential role in the pathology of neurological disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis, and epilepsy. Despite progress in the drug discovery and development of new drugs, drug delivery to the central nervous system (CNS) still represents the challenge due to the presence of the blood-brain barrier (BBB). Targeting NIF may require an adequate amount of drug to cross the BBB. Recently, the intranasal (IN) drug administration has attracted increasing attention as a reliable method to cross the BBB and treat neurological disorders. On the other hand, using optimized nanoparticles may improve the IN delivery limitations, increase the mucoadhesive properties, and prevent drug degradation. NPs can carry and deliver drugs to the CNS by bypassing the BBB. In this review, we described briefly the NIF as a pathologic feature of CNS diseases. The potential treatment possibilities with IN transfer of NP-loaded drugs will enhance the establishment of more efficient nanoformulations and delivery systems.

Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) suffer from depression at higher rates than the general population. An etiological trigger of depressive symptoms is theorised to be inflammation within the central nervous system. It is believed that heightened intestinal inflammation and dysfunction of the enteric nervous system (ENS) contribute to impaired intestinal permeability, which facilitates the translocation of intestinal enterotoxins into the blood circulation. Consequently, these may compromise the immunological and physiological functioning of distant non-intestinal tissues such as the brain. In vivo models of colitis provide evidence of increased blood-brain barrier permeability and enhanced central nervous system (CNS) immune activity triggered by intestinal enterotoxins and blood-borne inflammatory mediators. Understanding the immunological, physiological, and structural changes associated with IBD and neuroinflammation may aid in the development of more tailored and suitable pharmaceutical treatment for IBD-associated depression.

Lipopolysaccharide induced altered signaling pathways in various neurological disorders.

Neuroinflammation is defined as an inflammatory response within the brain or spinal cord, whereas the brain's innate immune system is triggered by various inflammatory challenges such as injury, infection, exposure to toxin (LPS) and ageing, which result in cognitive impairment and neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Lipopolysaccharide (LPS) is a main structural component of the outer membrane of gram-negative bacteria, widely used systematically to stimulate the immune system and to generate profound physiological and behavioural changes. It consists of three parts: lipid A, a core oligosaccharide and an O side chain. It is reported by several scientists that, besides the systemic alteration, LPS also induces neurodegeneration by promoting neuroinflammation upon binding with the stimulation of Toll-like receptor-4 (TLR4) receptors present on glial cells. The mammalian Toll-like receptor (TLR) family consists of 13 membranes and TLR was discovered as a crucial pattern recognition receptor (PPR) involved in the recognition of pathogen-associated molecular patterns (PAMPs). Future studies will show that damage/danger-associated molecular patterns (DAMPs) are recognised by the involvement of PPRs, generated by the host itself. The stimulation of TLR4 by lipopolysaccharide phosphorylates two signalling pathways, namely the MyD88-dependent pathway and the MyD88-independent pathway. This activation subsequently triggers the release of various pro-inflammatory cytokines that are necessary to activate innate immune responses, and then promotes neuroinflammation. In this review, we critically demonstrated the epidemiology of neuroinflammation, types of TLRs, the molecular mechanism of TLR4 and management of neuroinflammation.

Modulation of microglial activation by antidepressants.

BACKGROUND: Recent studies have suggested that microglial activation plays a key role in the pathogenesis of depression. In fact, neuroinflammation is associated with a phenotypic change of microglia, consisting of morphological differences, increased release of cytokines and oxidative stress products, which may contribute to the development and maintenance of depression. Antidepressants, including selective serotonin re-uptake inhibitors and serotonin-norepinephrine reuptake inhibitors, have been shown to act on the immune and oxidative stress mechanisms commonly found to be disrupted in depression. Thus, the inhibition of microglial activation may be one of the mechanisms through which they exert an antidepressant action. AIM: This is the first review summarising in vitro and ex vivo studies investigating the effects of different classes of antidepressants on microglia activation, by examining cellular changes and/or via measuring the production of immune and/or oxidative stress signalling molecules, in microglia models of neuroinflammation with either lipopolysaccharide (LPS) or cytokines. A total of 23 studies were identified, 18 using LPS stimulation and 5 using cytokines stimulation. RESULTS: Overall, the studies show that antidepressants, such as selective serotonin re-uptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants prevented microglial activation, including reduced microglial reactivity and decreased immune and oxidative stress products, in both models. However, specific antidepressants, such as bupropion and agomelatine did not prevent interferon-gamma (IFN-γ)-induced microglial activation; and for other antidepressants, including phenelzine, venlafaxine and sertraline, the results of different studies were inconsistent. CONCLUSIONS: Overall, results summarised in this review support the hypothesis that the action of at least certain classes of antidepressants may involve regulation of microglial activation, especially when in presence of increased levels of inflammation.

Varenicline improves cognitive impairment in a mouse model of mPFC ischemia: The possible roles of inflammation, apoptosis, and synaptic factors.

Ischemia in the medial prefrontal cortex (mPFC) causes cognitive impairment in stroke cases. This study aimed to examine the effects of varenicline as α7 and α4ß2 nicotine acetylcholine receptors (nAChRs) agonist, on cognitive impairment, inflammation, apoptosis, and synaptic dysfunction in mPFC ischemia. Mice were divided to three groups of control, sham, or photothrombotic mPFC ischemia model. The control and sham groups received 2 ml/kg of normal saline for a 14-day period. As well, the animals in the ischemia groups received normal saline (2 ml/kg) or varenicline at 0.1, 1, and 3 mg/kg doses for a 14-day period. Anxiety-like behaviors were then assessed by open field (OFT) and elevated plus-maze (EPM) tests. Memory was also evaluated using Morris water maze (MWM) and novel object recognition (NOR) tests. The levels of inflammatory (IL-1ß, TNF-α), apoptotic (Bax, caspase3, BCL-2), and synaptic (SYP, PSD-95, and GAP-43) proteins were examined using the western blot method. In addition, the histological evaluation was performed to assess tissue damage. The administration of Varenicline at the dose of 3 mg/kg reduced the IL-1ß, TNF-α, Bax, and caspase3 levels. Moreover, it increased BCL-2, SYP, PSD-95, and GAP-43 levels at the same dose and ameliorated memory impairment and anxiety-like behaviors in mPFC ischemic mice. Varenicline improved cognitive impairment by blocking inflammation and apoptosis, improving synaptic factors, and diminishing tissue damage in the mPFC ischemic mice.

Nervous system consequences of COVID-19.

Neurological symptoms highlight the need to understand pathophysiologic mechanisms.

Increased Intrathecal B and Plasma Cells in Patients With Anti-IgLON5 Disease: A Case Series.

BACKGROUND AND OBJECTIVES: Despite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5. METHODS: We identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder. RESULTS: Patients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab. DISCUSSION: Our findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.

A role of Na+, K+ -ATPase in spatial memory deficits and inflammatory/oxidative stress after recurrent concussion in adolescent rats.

Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1ß (IL 1ß), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na+,K+-ATPase activity (specifically isoform α2/3) followed by Km (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity.

BAY61­3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury.

Neuroinflammatory processes mediated by microglial activation and subsequent neuronal damage are the hallmarks of traumatic brain injury (TBI). As an inhibitor of the macrophage­inducible C­type lectin (Mincle)/spleen tyrosine kinase (Syk) signaling pathway, BAY61­3606 (BAY) has previously demonstrated anti­inflammatory effects on some pathological processes, such as acute kidney injury, by suppressing the inflammatory macrophage response. In the present study, the potential effects of BAY on microglial phenotype and neuroinflammation after TBI were investigated. BAY (3 mg/kg) was first administered into mice by intraperitoneal injection after TBI induction in vivo and microglia were also treated with BAY (2 µM) in vitro. The levels of inflammatory factors in microglia were assessed using reverse transcription­quantitative PCR and ELISA. Cortical neuron, myelin sheath, astrocyte and cerebrovascular endothelial cell markers were detected using immunofluorescence. The levels of components of the Mincle/Syk/NF­κB signaling pathway [Mincle, phosphorylated (p)­Syk and NF­κB], in addition to proteins associated with inflammation (ASC, caspase­1, TNF­α, IL­1ß and IL­6), apoptosis (Bax and Bim) and tight junctions (Claudin­5), were measured via western blotting and ELISA. Migration and chemotaxis of microglial cells were evaluated using Transwell and agarose spot assays. Neurological functions of the mice were determined in vivo using the modified neurological severity scoring system and a Morris water maze. The results of the present study revealed that the expression levels of proteins in the Mincle/Syk/NF­κB signaling pathway (including Mincle, p­Syk and p­NF­κB), inflammatory cytokines (TNF­α, IL­1ß and IL­6), proteins involved in inflammation (ASC and caspase­1), apoptotic markers (Bax and Bim) and the tight junction protein Claudin­5 were significantly altered post­TBI. BAY treatment reversed these effects in both the cerebral cortex extract­induced cell model and the controlled cortical impact mouse model. BAY was also revealed to suppress activation of the microglial proinflammatory phenotype and microglial migration. In addition, BAY effectively attenuated TBI­induced neurovascular unit damage and neurological function deficits. Taken together, these findings provided evidence that BAY may inhibit the Mincle/Syk/NF­κB signaling pathway in microglia; this in turn could attenuate microglia­mediated neuroinflammation and improve neurological deficits following TBI.

Metalloproteinases and their inhibitors in neurological disease.

Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade the extracellular matrix and are responsible for many physiological and pathological processes. We aim to review the MMP inhibition from a clinical perspective and its possible therapeutic use in the future. MMPs play a role in various neurodegenerative and cerebrovascular diseases such as large artery atherosclerosis and ischemic stroke; for example, MMPs increase blood-brain barrier permeability favoring neuroinflammation. Synthetic MMPs inhibitors have been tested mostly in oncological trials and failed to demonstrate efficacy; some of them were discontinued because of the severe adverse reactions. Tetracyclines, in submicrobial doses, act as an MMP inhibitor, although tetracyclines have not yet been proven effective in several neurological conditions in which they were tested against placebo; it is uncertain whether there may be a use for tetracyclines in cerebrovascular disease, as a neuroprotective agent or in dolichoectasia.

High frequency oscillations associate with neuroinflammation in low-grade epilepsy associated tumors.

OBJECTIVE: High frequency oscillations (HFOs) in intraoperative electrocorticography (ioECoG) are thought to be generated by hyperexcitable neurons. Inflammation may promote neuronal hyperexcitability. We investigated the relation between HFOs and inflammation in tumor-related epilepsy. METHODS: We identified HFOs (ripples 80-250 Hz, fast ripples 250-500 Hz) in the preresection ioECoG of 32 patients with low-grade tumors. Localization of recorded HFOs was classified based on magnetic resonance imaging reconstructions: in tumor, in resected non-tumorous area and outside the resected area. We tested if the following inflammatory markers in the tumor or peritumoral tissue were related to HFOs: activated microglia, cluster of differentiation 3 (CD3)-positive T-cells, interleukin 1-beta (IL1ß), toll-like receptor 4 (TLR4) and high mobility group box 1 protein (HMGB1). RESULTS: Tumors that generated ripples were infiltrated by more CD3-positive cells than tumors without ripples. Ripple rate outside the resected area was positively correlated with IL1ß/TLR4/HMGB1 pathway activity in peritumoral area. These two areas did not directly overlap. CONCLUSIONS: Ripple rates may be associated with inflammatory processes. SIGNIFICANCE: Our findings support that ripple generation and spread might be associated with synchronized fast firing of hyperexcitable neurons due to certain inflammatory processes. This pilot study provides arguments for further investigations in HFOs and inflammation.

Effects of exercise training on behavior and brain function after high dose isoproterenol-induced cardiac damage.

Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After 4 weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function.

Effects of ß-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.