Reactive Astrocytes Research Articles

Repair spinal cord injury with a versatile anti-oxidant and neural regenerative nanoplatform

Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen species (ROS) in the early and middle stages of SCI severely damage neurons, and most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads to a huge compromise in antioxidant treatment of SCI. Selenium nanoparticles (SeNPs) have excellent ROS scavenging bioactivity, but the toxicity control problem limits the therapeutic window. Here, we propose a synergistic therapeutic strategy of SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) to obtain synergistic ROS scavenging activity. Three different spatial structures of SeNPs@ZIF-8 were synthesized and coated with ferrostatin-1, a ferroptosis inhibitor (FSZ NPs), to achieve enhanced anti-oxidant and anti-ferroptosis activity without toxicity. FSZ NPs promoted the maintenance of mitochondrial homeostasis, thereby regulating the expression of inflammatory factors and promoting the polarization of macrophages into M2 phenotype. In addition, the FSZ NPs presented strong abilities to promote neuronal maturation and axon growth through activating the WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates the powerful and versatile bioactive functions of FSZ NPs for SCI treatment and offers inspiration for other neural injury diseases.

Transplantation of Pre‐Differentiated 3D Neural Spheroids in Decellularized Extracellular Matrix Microgels Promotes Neuronal Network Reconstruction and Functional Recovery after Severe Spinal Cord Contusion

AbstractTraumatic spinal cord injury (SCI) causes massive death of neurons in the spinal cords and almost complete neurological dysfunctions. Transplantation of neural stem/progenitor cells (NSPCs) is acknowledged as one of the viable SCI treatments for complementing lost neurons and neural network reconstruction. However, administration of NSPCs suffers from extremely low survival rate and uncontrolled differentiation of the transplanted cells, which impairs the therapeutic effects significantly. Herein, NSPCs are encapsulated in decellularized spinal cord matrix (DSCM) microgels using a customized microfluidic system, then the obtained NSPCs‐encapsulated DSCM microgels (NSPC@DSCM‐MGs) are subjected to neuronal differentiation induction. Consequently, the resulting pre‐mature 3D neural spheroids are injected into severely contused spinal cords in rats. The DSCM microgels effectively protected the transplanted cells from shear damage and the inflammatory microenvironment at the lesion site. The survival and accommodation of the pre‐differentiated NSPC@DSCM‐MGs actively contributed to axonal regeneration, inhibiting glial scar formation, as well as remodeling the microenvironment that facilitated endogenous cell recruitment and neuronal network reconstruction. Consequentially, administration of the neural spheroids led to maintenance of spinal cord integrity, and significantly improved hindlimb locomotor function. This biomaterial‐based transplantation strategy has shown unique assets in cell protection and cell‐fate manipulation, which holds great promise in versatile biomedical applications.

GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-β-Induced Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-β-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24h prior to intrahippocampal injection of amyloid-β. NFPS pretreatment prevented amyloid-β-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-β injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-β-induced hippocampal damage.

Decreased extrasynaptic δ-GABAA receptors in PNN-associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is associated with gradual memory loss and anxiety which affects ~75% of AD patients. This study investigated whether AD-associated anxiety correlated with modulation of extrasynaptic δ-subunit-containing GABAA receptors (δ-GABAARs) in experimental mouse models of AD. We combined behavioural experimental paradigms to measure cognition performance, and anxiety with neuroanatomy and molecular biology, using familial knock-in (KI) mouse models of AD that harbour β-amyloid (Aβ) precursor protein App (AppNL-F) with or without humanized microtubule-associated protein tau (MAPT), age-matched to wild-type control mice at three different age windows. AppNL-F KI and AppNL-F/MAPT AD models showed a similar magnitude of cognitive decline and elevated magnitude of anxiety correlated with neuroinflammatory hallmarks, including triggering receptor expressed on myeloid cells 2 (TREM2), reactive astrocytes and activated microglia consistent with accumulation of Aβ, tau and down-regulation of Wnt/β-catenin signalling compared to aged-matched WT controls. In both the CA1 region of the hippocampus and dentate gyrus, there was an age-dependent decline in the expression of δ-GABAARs selectively expressed in parvalbumin (PV)-expressing interneurons, encapsulated by perineuronal nets (PNNs) in the AD mouse models compared to WT mice. In vivo positive allosteric modulation of the δ-GABAARs, using a δ-selective-compound DS2, decreased the level of anxiety in the AD mouse models, which was correlated with reduced hallmarks of neuroinflammation, and 'normalisation' of the expression of δ-GABAARs. Our data show that the δ-GABAARs could potentially be targeted for alleviating symptoms of anxiety, which would greatly improve the quality of life of AD individuals.

MiR-540-3p partially recovers the locomotor function of spinal cord injury mice by targeting SIX4/Yap1 and inactivation of astrocytes

ABSTRACT Background Spinal cord injury (SCI) lacks therapeutic reagents. miRNAs are responsible for mesenchymal stem cells (MSCs) therapy in spinal cord injury. Purpose To discover the underlying therapeutic miRNA target and its mechanism for the treatment of SCI. Method Two RNA sequence datasets were retrieved from the GEO Datasets database which was accessed on 30 December 2023. The targets of the top 2 ranked miRNAs (miR-540-3p and miR-433-5p) were analyzed using online databases (miRDB, miRMap, TargetScan and STRING database) and both miRNAs were screened by cell counting kit-8 (CCK-8) assay. Then, transfection and local injection of miR-540-3p were performed to examine the capacity of secretion of astrocytes and the locomotor function of SCI mice. Results The significantly high levels of miR-540-3p/433-5p were revealed. Transfection of miR-540-3p conferred inactivation of reactive astrocytes and weakened the capacity of secreting inflammatory cytokines of astrocytes. miR-433-5p was proven to not impact the proliferation of astrocytes. Co-culture of culture supernate from astrocytes transfected with miR-540-3p and neurons demonstrated the significantly preserved neurite length and decreased apoptotic level of neurons. Meanwhile, sine oculis homeobox (SIX4)/Yap1, as the target of miR-540-3p, is critical for abrogating inflammatory damage of neurons in vivo and in vitro, decreasing glial scar, and recovering locomotor function of spinal cord injury mice. Furthermore, SCI mice receiving a local injection of miR-540-3p showed smaller and lighter bladder volume and higher limb strength, but the period from urinary retention to autonomous urination of SCI mice showed no significance. Conclusions Conclusively, miR-540 discovered from hypoxia-treated exosomes suppresses the inflammatory cytokines secreted by reactive astrocytes, partially preserves the neuronal function of spinal cord injury mice, through the SIX4/Yap1 signalling pathway.

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice.

Neuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals. Previous studies have shown early hyperexcitability in the hippocampal CA3 region in male A30P mice at 2-4 months of age, therefore, in the current study we have immunostained this region for markers of neuronal activity (c-Fos), reactive astrocytes (glial fibrillary acidic protein, GFAP), microglia (ionizing calcium binding adapter protein 1, Iba-1) and reactive microglia (inducible nitric oxide synthase, iNOS). We found an interesting biphasic change in the expression of c-Fos in A30P mice with high expression at 1 month, consistent with early onset of hyperexcitability, but lower expression from 2-4 months in male A30P mice compared to wild-type (WT) controls, possibly indicating chronic hyperexcitability. Neuroinflammation was indicated by significant increases in the % area of GFAP and the number of Iba-1+ cells that expressed iNOS immunoreactivity in the CA3 region in 2-4 months A30P male mice compared to WT controls. A similar increase in % area of GFAP was observed in female A30P mice, however, the Iba-1 count was not different between female WT and A30P mice. In WT mice aged 2-4 months only 4.6% of Iba-1+ cells co-expressed iNOS. In contrast, in age matched A30P mice 87% of cells co-expressed Iba-1 and iNOS. Although there was no difference in GFAP immunoreactivity at 1 month, Iba-1/iNOS co-expression was also increased in a cohort of 1 month old A30P mice. Abnormal hα-syn expression in A30P mice caused early changes in network excitability, as indicated by c-Fos expression, and neuroinflammation which might contribute to disease progression.

Acid Neutralization by Composite Lysine Nanoparticles for Spinal Cord Injury Recovery through Mitigating Mitochondrial Dysfunction.

After spinal cord injury (SCI), significant alterations in the tissue microenvironment lead to mitochondrial dysfunction, inducing apoptosis and inhibiting the remodeling of neural circuits, thereby impeding recovery. Although previous studies have demonstrated a marked decrease in pH at the injury site, creating an acidic microenvironment, the impact of improving this acidic microenvironment on SCI recovery has not been investigated. This study prepared a lysine@hollow mesoporous silica nanoparticle/gelatin methacrylate (GelMA) (L@H/G) composite hydrogel. The L@H/G composite hydrogel was demonstrated to release lysine and efficiently improve the acidic microenvironment slowly. Significantly, the composite hydrogel reduced cell apoptosis, promoted nerve regeneration, inhibited glial scar formation, and ultimately enhanced motor function recovery in mice with SCI. Mechanistically, the L@H/G hydrogel improved the mitochondrial tricarboxylic acid (TCA) cycle and fatty acid metabolism, restoring energy supply and facilitating mitochondrial function recovery. To the best of our knowledge, this is the first report confirming that improving the acidic microenvironment could promote SCI repair, providing a potential therapeutic strategy for SCI.

Cell adhesion molecule CD44 is dispensable for reactive astrocyte activation during prion disease

Prion diseases are fatal, infectious, neurodegenerative disorders resulting from accumulation of misfolded cellular prion protein in the brain. Early pathological changes during CNS prion disease also include reactive astrocyte activation with increased CD44 expression, microgliosis, as well as loss of dendritic spines and synapses. CD44 is a multifunctional cell surface adhesion and signalling molecule which is considered to play roles in astrocyte morphology and the maintenance of dendritic spine integrity and synaptic plasticity. However, the role of CD44 in prion disease was unknown. Here we used mice deficient in CD44 to determine the role of CD44 during prion disease. We show that CD44-deficient mice displayed no difference in their response to CNS prion infection when compared to wild type mice. Furthermore, the reactive astrocyte activation and microgliosis that accompanies CNS prion infection was unimpaired in the absence of CD44. Together, our data show that although CD44 expression is upregulated in reactive astrocytes during CNS prion disease, it is dispensable for astrocyte and microglial activation and the development of prion neuropathogenesis.

Up-regulating GABA transporter-3 in the zona incerta prevents surgery-induced memory impairment in mice

Clinical surgery can lead to severe neuroinflammation and cognitive dysfunctions. It has been reported that astrocytes mediate memory formation and postoperative cognitive dysfunction (POCD), however, the thalamic mechanism of astrocytes in mediating POCD remains unknown. Here, we report that reactive astrocytes in zona incerta (ZI) mediate surgery-induced recognition memory impairment in male mice. Immunostaining results showed that astrocytes are activated with GABA transporter-3 (GAT-3) being down-expressed, and neurons were suppressed in the ZI. Besides, our work revealed that reactive astrocytes caused increased tonic current in ZI neurons. Up-regulating the expression of GAT-3 in astrocytes ameliorates surgery-induced recognition memory impairment. Together, our work demonstrates that the reactive astrocytes in the ZI play a crucial role in surgery-induced memory impairment, which provides a new target for the treatment of surgery-induced neural dysfunctions.

Mechanobiological Modulation of In Vitro Astrocyte Reactivity Using Variable Gel Stiffness.

After traumatic brain injury, the brain extracellular matrix undergoes structural rearrangement due to changes in matrix composition, activation of proteases, and deposition of chondroitin sulfate proteoglycans by reactive astrocytes to produce the glial scar. These changes lead to a softening of the tissue, where the stiffness of the contusion "core" and peripheral "pericontusional" regions becomes softer than that of healthy tissue. Pioneering mechanotransduction studies have shown that soft substrates upregulate intermediate filament proteins in reactive astrocytes; however, many other aspects of astrocyte biology remain unclear. Here, we developed a platform for the culture of cortical astrocytes using polyacrylamide (PA) gels of varying stiffness (measured in Pascal; Pa) to mimic injury-related regions in order to investigate the effects of tissue stiffness on astrocyte reactivity and morphology. Our results show that substrate stiffness influences astrocyte phenotype; soft 300 Pa substrates led to increased GFAP immunoreactivity, proliferation, and complexity of processes. Intermediate 800 Pa substrates increased Aggrecan+, Brevican+, and Neurocan+ astrocytes. The stiffest 1 kPa substrates led to astrocytes with basal morphologies, similar to a physiological state. These results advance our understanding of astrocyte mechanotransduction processes and provide evidence of how substrates with engineered stiffness can mimic the injury microenvironment.

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aβ) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aβ pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2–4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aβ pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1β, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

Oligodendrocyte Progenitors in Glial Scar: A Bet on Remyelination.

Oligodendrocyte progenitor cells (OPCs) represent a subtype of glia, giving rise to oligodendrocytes, the myelin-forming cells in the central nervous system (CNS). While OPCs are highly proliferative during development, they become relatively quiescent during adulthood, when their fate is strictly influenced by the extracellular context. In traumatic injuries and chronic neurodegenerative conditions, including those of autoimmune origin, oligodendrocytes undergo apoptosis, and demyelination starts. Adult OPCs become immediately activated; they migrate at the lesion site and proliferate to replenish the damaged area, but their efficiency is hampered by the presence of a glial scar-a barrier mainly formed by reactive astrocytes, microglia and the deposition of inhibitory extracellular matrix components. If, on the one hand, a glial scar limits the lesion spreading, it also blocks tissue regeneration. Therapeutic strategies aimed at reducing astrocyte or microglia activation and shifting them toward a neuroprotective phenotype have been proposed, whereas the role of OPCs has been largely overlooked. In this review, we have considered the glial scar from the perspective of OPCs, analysing their behaviour when lesions originate and exploring the potential therapies aimed at sustaining OPCs to efficiently differentiate and promote remyelination.

A convenient model of serum-induced reactivity of human astrocytes to investigate astrocyte-derived extracellular vesicles.

Extracellular vesicles (EVs) are secreted by all cells in the CNS, including neurons and astrocytes. EVs are lipid membrane enclosed particles loaded with various bioactive cargoes reflecting the dynamic activities of cells of origin. In contrast to neurons, the specific role of EVs released by astrocytes is less well understood, partly due to the difficulty in maintaining primary astrocyte cultures in a quiescent state. The aim of this study was to establish a human serum-free astrocyte culture system that maintains primary astrocytes in a quiescent state to study the morphology, function, and protein cargoes of astrocyte-derived EVs. Serum-free medium with G5 supplement and serum-supplemented medium with 2% FBS were compared for the culture of commercially available human primary fetal astrocytes. Serum-free astrocytes displayed morphologies similar to in vivo astrocytes, and surprisingly, higher levels of astrocyte markers compared to astrocytes chronically cultured in FBS. In contrast, astrocyte and inflammatory markers in serum-free astrocytes were upregulated 24 h after either acute 2% FBS or cytokine exposure, confirming their capacity to become reactive. Importantly, this suggests that distinct signaling pathways are involved in acute and chronic astrocyte reactivity. Despite having a similar morphology, chronically serum-cultured astrocyte-derived EVs (ADEVs) were smaller in size compared to serum-free ADEVs and could reactivate serum-free astrocytes. Proteomic analysis identified distinct protein datasets for both types of ADEVs with enrichment of complement and coagulation cascades for chronically serum-cultured astrocyte-derived EVs, offering insights into their roles in the CNS. Collectively, these results suggest that human primary astrocytes cultured in serum-free medium bear similarities with in vivo quiescent astrocytes and the addition of serum induces multiple morphological and transcriptional changes that are specific to human reactive astrocytes and their ADEVs. Thus, more emphasis should be made on using multiple structural, molecular, and functional parameters when evaluating ADEVs as biomarkers of astrocyte health.

Microglia aggravate white matter injury via C3/C3aR pathway after experimental subarachnoid hemorrhage

The activation of glial cells is intimately associated with the pathophysiology of neuroinflammation and white matter injury (WMI) during both acute and chronic phases following subarachnoid hemorrhage (SAH). The complement C3a receptor (C3aR) has a dual role in modulating inflammation and contributes to neurodevelopment, neuroplasticity, and neurodegeneration. However, its impact on WMI in the context of SAH remains unclear. In this study, 175 male C57BL/6J mice underwent SAH through endovascular perforation. Oxyhemoglobin (oxy-Hb) was employed to simulate SAH in vitro. A suite of techniques, including immunohistochemistry, transcriptomic sequencing, and a range of molecular biotechnologies, were utilized to evaluate the activation of the C3-C3aR pathway on microglial polarization and WMI. Results revealed that post-SAH abnormal activation of microglia was accompanied by upregulation of complement C3 and C3aR. The inhibition of C3aR decreased abnormal microglial activation, attenuated neuroinflammation, and ameliorated WMI and cognitive deficits following SAH. RNA-Seq indicated that C3aR inhibition downregulated several immune and inflammatory pathways and mitigated cellular injury by reducing p53-induced death domain protein 1 (Pidd1) and Protein kinase RNA-like ER kinase (Perk) expression, two factors mainly function in sensing and responding to cellular stress and endoplasmic reticulum (ER) stress. The deleterious effects of the C3-C3aR axis in the context of SAH may be related to endoplasmic reticulum (ER) stress-dependent cellular injury and inflammasome formation. Agonists of Perk can exacerbate the cellular injury and neuroinflammation, which was attenuated by C3aR inhibition after SAH. Additionally, intranasal administration of C3a during the subacute phase of SAH was found to decrease astrocyte reactivity and alleviate cognitive deficits post-SAH. This research deepens our understanding of the complex pathophysiology of WMI following SAH and underscores the therapeutic potential of C3a treatment in promoting white matter repair and enhancing functional recovery prognosis. These insights pave the way for future clinical application of C3a-based therapies, promising significant benefits in the treatment of SAH and its related complications.

Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation

Major depressive disorder (MDD) is a global health burden characterized by persistent low mood, deprivation of pleasure, recurrent thoughts of death, and physical and cognitive deficits. The current understanding of the pathophysiology of MDD is lacking, resulting in few rapid and effective antidepressant therapies. Recent studies have pointed to the sigma-1 (σ-1) receptor as a potential rapid antidepressant target; σ-1 agonists have shown promise in a variety of preclinical depression models. Hypidone hydrochloride (YL-0919), an independently developed antidepressant by our institute with faster onset of action and low rate of side effects, has recently emerged as a highly selective σ-1 receptor agonist; however, its underlying astrocyte-specific mechanism is unknown. In this study, we investigated the effect of YL-0919 treatment on gene expression in the prefrontal cortex of depressive-like mice by single-cell RNA sequencing. Furthermore, we knocked down σ-1 receptors on astrocytes in the medial prefrontal cortex of mice to explore the effects of YL-0919 on depressive-like behavior and neuroinflammation in mice. Our results demonstrated that astrocyte-specific knockdown of σ-1 receptor resulted in depressive-like behavior in mice, which was reversed by YL-0919 administration. In addition, astrocytic σ-1 receptor deficiency led to activation of the NF-κB inflammatory pathway, and crosstalk between reactive astrocytes and activated microglia amplified neuroinflammation, exacerbating stress-induced neuronal apoptosis. Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs.

Nimodipine inhibits spreading depolarization, ischemic injury, and neuroinflammation in mouse live brain slice preparations

Nimodipine is used to prevent delayed ischemic deficit in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarization (SD) is recognized as a factor in the pathomechanism of aSAH and other acute brain injuries. Although nimodipine is primarily known as a cerebral vasodilator, it may have a more complex mechanism of action due to the expression of its target, the L-type voltage-gated calcium channels (LVGCCs) in various cells in neural tissue. This study was designed to investigate the direct effect of nimodipine on SD, ischemic tissue injury, and neuroinflammation. SD in control or nimodipine-treated live mouse brain slices was induced under physiological conditions using electrical stimulation, or by subjecting the slices to hypo-osmotic stress or mild oxygen-glucose deprivation (mOGD). SD was recorded applying local field potential recording or intrinsic optical signal imaging. Histological analysis was used to estimate tissue injury, the number of reactive astrocytes, and the degree of microglia activation. Nimodipine did not prevent SD occurrence in mOGD, but it did reduce the rate of SD propagation and the cortical area affected by SD. In contrast, nimodipine blocked SD occurrence in hypo-osmotic stress, but had no effect on SD propagation. Furthermore, nimodipine prevented ischemic injury associated with SD in mOGD. Nimodipine also exhibited anti-inflammatory effects in mOGD by reducing reactive astrogliosis and microglial activation. The results demonstrate that nimodipine directly inhibits SD, independent of nimodipine's vascular effects. Therefore, the use of nimodipine may be extended to treat acute brain injuries where SD plays a central role in injury progression.

Acute astrocytic reaction is associated with 3-month functional outcome after stroke treated with endovascular therapy

Acute astrocytic reaction is associated with 3-month functional outcome after stroke treated with endovascular therapy

Microstructural associations between locus coeruleus, cortical, and subcortical regions are modulated by astrocyte reactivity: a 7T MRI adult lifespan study.

The locus coeruleus-norepinephrine system plays a key role in supporting brain health along the lifespan, notably through its modulatory effects on neuroinflammation. Using ultra-high field diffusion magnetic resonance imaging, we examined whether microstructural properties (neurite density index and orientation dispersion index) in the locus coeruleus were related to those in cortical and subcortical regions, and whether this was modulated by plasma glial fibrillary acidic protein levels, as a proxy of astrocyte reactivity. In our cohort of 60 healthy individuals (30 to 85yr, 50% female), higher glial fibrillary acidic protein correlated with lower neurite density index in frontal cortical regions, the hippocampus, and the amygdala. Furthermore, under higher levels of glial fibrillary acidic protein (above ~ 150pg/mL for cortical and ~ 145pg/mL for subcortical regions), lower locus coeruleus orientation dispersion index was associated with lower orientation dispersion index in frontotemporal cortical regions and in subcortical regions. Interestingly, individuals with higher locus coeruleus orientation dispersion index exhibited higher orientation dispersion index in these (sub)cortical regions, despite having higher glial fibrillary acidic protein levels. Together, these results suggest that the interaction between locus coeruleus-norepinephrine cells and astrocytes can signal a detrimental or neuroprotective pathway for brain integrity and support the importance of maintaining locus coeruleus neuronal health in aging and in the prevention of age-related neurodegenerative diseases.

Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions.

Astrocytes are the most abundant type of glial cell in the central nervous system. Upon injury and inflammation, astrocytes become reactive and undergo morphological and functional changes. Depending on their phenotypic classification as A1 or A2, reactive astrocytes contribute to both neurotoxic and neuroprotective responses, respectively. However, this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries. Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles, which emphasizes the heterogeneous nature of their reactivity. Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types, releasing cytokines, and influencing the immune response. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior, as evidenced by in silico , in vitro , and in vivo results. In astrocytes, inflammatory cues trigger a cascade of molecular events, where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses. Here, we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation. We highlight the involvement of various signaling pathways that regulate astrocyte reactivity, including the PI3K/AKT/mammalian target of rapamycin (mTOR), α v β 3 integrin/PI3K/AKT/connexin 43, and Notch/PI3K/AKT pathways. While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage, evidence suggests that activating this pathway could also yield beneficial outcomes. This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation. The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior. The findings should then be validated using in vivo models to ensure real-life relevance. The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage, although further studies are required to fully comprehend its role due to varying factors such as different cell types, astrocyte responses to inflammation, and disease contexts. Specific strategies are clearly necessary to address these variables effectively.

Combinatorial therapies for spinal cord injury repair.

Spinal cord injuries have profound detrimental effects on individuals, regardless of whether they are caused by trauma or non-traumatic events. The compromised regeneration of the spinal cord is primarily attributed to damaged neurons, inhibitory molecules, dysfunctional immune response, and glial scarring. Unfortunately, currently, there are no effective treatments available that can fully repair the spinal cord and improve functional outcomes. Nevertheless, numerous pre-clinical approaches have been studied for spinal cord injury recovery, including using biomaterials, cells, drugs, or technological-based strategies. Combinatorial treatments, which target various aspects of spinal cord injury pathophysiology, have been extensively tested in the last decade. These approaches aim to synergistically enhance repair processes by addressing various obstacles faced during spinal cord regeneration. Thus, this review intends to provide scientists and clinicians with an overview of pre-clinical combinatorial approaches that have been developed toward the solution of spinal cord regeneration as well as update the current knowledge about spinal cord injury pathophysiology with an emphasis on the current clinical management.