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Innate immunity mediated by microglia appears to play a crucial role in initiating and propagating seizure-induced inflammatory responses. To address the role of activated microglia in the pathogenesis of childhood epilepsy, we first examined the time course of microglia activation following kainic acid-induced status epilepticus (KA-SE) in Cx3cr1(...
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... 7 daily doses of minocycline treatment after KA-SE at P25 (first dose given on the day of KA-SE), mice were sacrificed at P32 and microglia activation quantified by comparing presence or absence of microglia aggregates and by the percent area of fluorescence ( Figure 3). Similar to the above findings on the time course experiment (3.1), microglia activation remained significantly increased in KA-treated animals (KS) compared to control animals (SS) 7 days after injections (SS vs. KS; p<0.001) and this persistent microglia activation was significantly inhibited by minocycline (KS vs. KM; p<0.05). ...
Context 2
... semi-synthetic tetracycline derivative, minocycline, has potent anti-inflammatory effects independent from its microbicidal properties, as it is well known to inhibit macrophage and microglia activation (Henry et al., 2008;Pabreja et al., 2011). In our two-hit seizure model, minocycline mitigated seizure-induced microglia activation rather than completely block inflammatory response (Figure 3). Minocycline treatment after KA-SE, therefore, may have promoted the shift from a pathologic to a physiologic, homeostatic glial response. ...
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Minocycline is a commonly used antibiotic of the tetracycline famil...
Citations
... Some of the first studies investigating viral encephalitis-induced seizures in the Theiler's Murine Encephalomyelitis Virus model (TMEV) confirmed that IL-6-producing cells are pivotal for seizure development (Kirkman et al., 2010;: Minocycline treatment as well as IL-6 deficiency modulated phagocyte activation and infiltration and reduced seizures (Cusick et al., 2013). Similarly, minocycline decreased microglial activation in a kainate-induced early-life SE model (Abraham et al., 2012). Treated mice were less susceptible to a second hit seizure in later life compared to controls (Abraham et al., 2012). ...
... Similarly, minocycline decreased microglial activation in a kainate-induced early-life SE model (Abraham et al., 2012). Treated mice were less susceptible to a second hit seizure in later life compared to controls (Abraham et al., 2012). Furthermore, if minocycline was applied before kainate-induced SE, apoptosis in the hippocampus was reduced (Heo et al., 2006). ...
Phagocytes maintain homeostasis in a healthy brain. Upon injury, they are essential for repairing damaged tissue, recruiting other immune cells, and releasing cytokines as the first line of defense. However, there seems to be a delicate balance between the beneficial and detrimental effects of their activation in a seizing brain. Blocking the infiltration of peripheral phagocytes (macrophages) or their depletion can partially alleviate epileptic seizures and prevent the death of neurons in experimental models of epilepsy. However, the depletion of resident phagocytes in the brain (microglia) can aggravate disease outcomes. This review describes the role of resident microglia and peripheral infiltrating monocytes in animal models of acutely triggered seizures and epilepsy. Understanding the roles of phagocytes in ictogenesis and the time course of their activation and involvement in epileptogenesis and disease progression can offer us new biomarkers to identify patients at risk of developing epilepsy after a brain insult, as well as provide novel therapeutic targets for treating epilepsy.
... However, many of the therapeutics explored in these studies have shown marginal, if any, benefit in human trials. For example, tetracycline has been shown to inhibit microglial activation and was even shown in in vivo studies to reduce glioma proliferation [59][60][61][62][63][64]. This ultimately resulted in three clinical trials (NCT01580969, NCT02272270, and NCT02770378); however, each showed no clear clinical benefit. ...
Glioblastoma (GBM) is one of the most aggressive and devastating primary brain tumors, with a median survival of 15 months following diagnosis. Despite the intense treatment regimen which routinely includes maximal safe neurosurgical resection followed by adjuvant radio- and chemotherapy, the disease remains uniformly fatal. The poor prognosis associated with GBM is multifactorial owing to factors such as increased proliferation, angiogenesis, and metabolic switching to glycolytic pathways. Critically, GBM-mediated local and systemic immunosuppression result in inadequate immune surveillance and ultimately, tumor-immune escape. Microglia-the resident macrophages of the central nervous system (CNS)-play crucial roles in mediating the local immune response in the brain. Depending on the specific pathological cues, microglia are activated into either a pro-inflammatory, neurotoxic phenotype, known as M1, or an anti-inflammatory, regenerative phenotype, known as M2. In either case, microglia secrete corresponding pro- or anti-inflammatory cytokines and chemokines that either promote or hinder tumor growth. Herein, we review the interplay between GBM cells and resident microglia with a focus on contemporary studies highlighting the effect of GBM on the subtypes of microglia expressed, the associated cytokines/chemokines secreted, and ultimately, their impact on tumor pathogenesis. Finally, we explore how understanding the intricacies of the tumor-immune landscape can inform novel immunotherapeutic strategies against this devastating disease.
... Inflammatory processes initiated by a brain insult could lead to functional impairments and, ultimately, psychiatric symptoms (Vezzani et al., 2013). In ELS models, long-term glial activation has been related to behavioral impairments and epileptogenesis (de Oliveira et al., 2008), while treatment with inflammatory inhibitors resulted in reductions of GFAP and cognitive impairments (Abraham et al., 2012;Somera-Molina et al., 2007). High levels of pro-inflammatory substances and neuroinflammation have been documented in animal models and patients with schizophrenia and ASD (Prata et al., 2017;Vezzani et al., 2013). ...
Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.
... Inflammatory processes initiated by a brain insult could lead to functional impairments and, ultimately, psychiatric symptoms (Vezzani et al., 2013). In ELS models, long-term glial activation has been related to behavioral impairments and epileptogenesis (de Oliveira et al., 2008), while treatment with inflammatory inhibitors resulted in reductions of GFAP and cognitive impairments (Abraham et al., 2012;Somera-Molina et al., 2007). High levels of pro-inflammatory substances and neuroinflammation have been documented in animal models and patients with schizophrenia and ASD (Prata et al., 2017;Vezzani et al., 2013). ...
Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC- PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.
... Inflammatory processes initiated by a brain insult could lead to functional impairments and, ultimately, psychiatric symptoms (Vezzani et al., 2013 ). In ELS models, long-term glial activation has been related to behavioral impairments and epileptogenesis (De Oliveira et al., 2008b ), while treatment with inflammatory inhibitors resulted in reductions of GFAP and cognitive impairments (Abraham et al., 2012 ;Somera-Molina et al., 2007 ). High levels of pro-inflammatory substances and neuroinflammation have been documented in animal models and patients with schizophrenia and ASD (Prata et al., 2017 ;Vezzani et al., 2013 ). ...
Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.
... As a highly brain-penetrant tetracycline, minocycline has been shown to have anti-inflammatory and neuroprotective properties in epileptic animal models. [16][17][18] Several researches have reported the ameliorative effect of minocycline on cognition by influencing dendrite and dendritic spines 19,20 or microglia 21 in different disease models. In the present study, we used a kainic acid-induced status epilepticus (SE) mouse model to analyze the dynamic alterations of M1 and M2 microglia and the expression levels of several markers of microglial phenotypes and investigated the morphology of dendrites and dendritic spins in the hippocampus at different stages after SE in the immature brain. ...
... 21 It has been demonstrated that minocycline could decrease the number of reactivated microglia in SE models induced by KA and pilocarpine. 16,17 However, few studies related to epilepsy have focused on the effects of minocycline on M1/M2 microglial reactivation. In this study, minocycline could inhibit M1 microglia reactivation at the three time points and promote M2 microglia reactivation after acute SE, indicating the anti-inflammatory and neuroprotective effects of minocycline on KA-induced brain injury by switching the M1/M2 phenotype. ...
Purpose
This study aimed to investigate whether minocycline could influence alterations of microglial subtypes, the morphology of dendrites and dendritic spines, the microstructures of synapses and synaptic proteins, or even cognition outcomes in immature male mice following status epilepticus (SE) induced by kainic acid.
Methods
Golgi staining was performed to visualize the dendrites and dendritic spines of neurons of the hippocampus. The microstructures of synapses and synaptic proteins were observed using transmission electron microscopy and western blotting analysis, respectively. Microglial reactivation and their markers were evaluated using flow cytometry. The Morris water maze (MWM) test was used to analyze spatial learning and memory ability.
Results
Significant partial spines increase (predominate in thin spines) was observed in the dendrites of neurons after acute SE and partial loss (mainly in thin spines) was presented by days 14 and 28 post‐SE. The postsynaptic ultrastructure was impaired on the 7th and 14th days after SE. The proportion of M1 microglia increased significantly only after acute SE Similarly, the proportion of M2 microglia increased in the acute stage with high expression levels of all surface markers. In contrast, a decrease in M2 microglia and their markers was noted by day 14 post‐SE. Minocycline could reverse the changes in dendrites and synaptic proteins caused by SE, and increase the levels of synaptic proteins. Meanwhile, minocycline could inhibit the reactivation of M1 microglia and the expression of their markers, except for promoting CD200R. In addition, treatment with minocycline could regulate the expression of M2 microglia and their surface markers, as well as ameliorating the impaired spatial learning and memory on the 28th day after SE.
Conclusions
Dendritic spines and microglia are dynamically changed after SE. Minocycline could ameliorate the impaired cognition in the kainic acid‐induced mouse model by decreasing the damage to dendrites and altering microglial reactivation.
... Microglia are the primary brain-resident inflammation-competent cells. Conflicting experimental results suggest that microglia either promote seizures (Abraham et al., 2012;Di Nunzio et al., 2021;Eun et al., 2015;Kim et al., 2015) or dampen neuronal hyperactivity (Cserép et al., 2020;Kato et al., 2016;Li et al., 2012;Merlini et al., 2021) and perform seizure-limiting functions as evidenced when they are eliminated by pharmacogenetic approaches (Mirrione et al., 2010;Wu et al., 2020). However, concerns about these pharmacogenetic elimination approaches have arisen with evidence that they cause disrupted structural brain features, behavioral, and cellular abnormalities, as well as increased cytokine release and glial reactivity (Bedolla et al., 2022;Rubino et al., 2018). ...
... The precise role of microglia in seizure disorders has been elusive with suggested beneficial (Liu et al., 2020;Mirrione et al., 2010;Waltl et al., 2018;Wan et al., 2020;Wu et al., 2020;Zhao et al., 2020) and detrimental roles (Abraham et al., 2012;Di Nunzio et al., 2021;Eun et al., 2015;Kim et al., 2015). Using an approach that lacks inflammatory sequelae, glial reactivity, or brain structural aberrations in three different seizure paradigms, we provide comprehensive evidence for beneficial roles for microglia in mitigating seizures. ...
Seizure disorders are common, affecting both the young and the old. Currently available antiseizure drugs are ineffective in a third of patients and have been developed with a focus on known neurocentric mechanisms, raising the need for investigations into alternative and complementary mechanisms that contribute to seizure generation or its containment. Neuroinflammation, broadly defined as the activation of immune cells and molecules in the central nervous system (CNS), has been proposed to facilitate seizure generation, although the specific cells involved in these processes remain inadequately understood. The role of microglia, the primary inflammation-competent cells of the brain, is debated since previous studies were conducted using approaches that were less specific to microglia or had inherent confounds. Using a selective approach to target microglia without such side effects, we show a broadly beneficial role for microglia in limiting chemoconvulsive, electrical, and hyperthermic seizures and argue for a further understanding of microglial contributions to contain seizures.
... The precise role of microglia in seizure disorders has been elusive with suggested beneficial (Liu et al., 2020;Mirrione et al., 2010;Waltl et al., 2018;Wan et al., 2020;Wu et al., 2020;Zhao et al., 2020) and detrimental roles (Abraham et al., 2012;Di Nunzio et al., 2021;Eun et al., 2015;Kim et al., 2015). Using an approach that lacks inflammatory sequelae, glial reactivity, or brain structural aberrations in three different seizure paradigms, we provide comprehensive evidence for beneficial roles for microglia in mitigating seizures. ...
Seizure disorders are common, affecting both the young and the old. Currently available antiseizure drugs are ineffective in a third of patients and have been developed with a focus on known neurocentric mechanisms, raising the need for investigations into alternative and complementary mechanisms that contribute to seizure generation or its containment. Neuroinflammation, broadly defined as the activation of immune cells and molecules in the central nervous system (CNS), has been proposed to facilitate seizure generation, although the specific cells involved in these processes remain inadequately understood. The role of microglia, the primary inflammation-competent cells of the brain, is debated since previous studies were conducted using approaches that were less specific to microglia or had inherent confounds. Using a selective approach to target microglia without such side effects, we show a broadly beneficial role for microglia in limiting chemoconvulsive, electrical, and hyperthermic seizures and argue for a further understanding of microglial contributions to contain seizures.
... Although our results support previous findings in rodent models of epilepsy whereby pharmacological inhibition of pro-inflammatory cytokines released by glial cells leads to seizure suppression, [44][45][46]79,80 we provide direct genetic evidence that specifically reducing the IIR in glia of an animal seizure model can suppress exacerbation of the seizure disorder. The use of a fly model allowed us to specifically assess the involvement of innate immune system activation in seizure generation, because unlike jawed vertebrates, flies do not utilize an adaptive immune system. ...
Previous work in our laboratory has shown that mutations in prickle (pk) cause myoclonic-like seizures and ataxia in Drosophila, similar to what is observed in humans carrying mutations in orthologous PRICKLE genes. Here, we show that pk mutant brains show elevated, sustained neuronal cell death that correlates with increasing seizure penetrance, as well as an upregulation of mitochondrial oxidative stress and innate immune response (IIR) genes. Moreover, flies exhibiting more robust seizures show increased levels of IIR-associated target gene expression suggesting they may be linked. Genetic knockdown in glia of either arm of the IIR (Immune Deficiency [Imd] or Toll) leads to a reduction in neuronal death, which in turn suppresses seizure activity, with oxidative stress acting upstream of IIR. These data provide direct genetic evidence that oxidative stress in combination with glial-mediated IIR leads to progression of an epilepsy disorder.
... This is in line with our behavioral and electrophysiological results indicating a recovery within the first week after stress. Accordingly, previous studies found that minocycline action depends on the inflammatory status and that microglial reactivity is mainly affected in the short-term after stress, when an immune system response occurs [68,[81][82][83]. However, here, the relation between inflammatory response and behavioral profile is still speculative because further data on microglial functional states at different time points are still warranted. ...
Major depressive disorder (MDD) is a chronic, recurring, and potentially life-threatening illness, which affects over 300 million people worldwide. MDD affects not only the emotional and social domains but also cognition. However, the currently available treatments targeting cognitive deficits in MDD are limited. Minocycline, an antibiotic with anti-inflammatory properties recently identified as a potential antidepressant, has been shown to attenuate learning and memory deficits in animal models of cognitive impairment. Here, we explored whether minocycline recovers the deficits in cognition in a mouse model of depression. C57BL6/J adult male mice were exposed to two weeks of chronic unpredictable mild stress to induce a depressive-like phenotype. Immediately afterward, mice received either vehicle or minocycline for three weeks in standard housing conditions. We measured anhedonia as a depressive-like response, and place learning to assess cognitive abilities. We also recorded long-term potentiation (LTP) as an index of hippocampal functional plasticity and ran immunohistochemical assays to assess microglial proportion and morphology. After one week of treatment, cognitive performance in the place learning test was significantly improved by minocycline, as treated mice displayed a higher number of correct responses when learning novel spatial configurations. Accordingly, minocycline-treated mice displayed higher LTP compared to controls. However, after three weeks of treatment, no difference between treated and control animals was found for behavior, neural plasticity, and microglial properties, suggesting that minocycline has a fast but short effect on cognition, without lasting effects on microglia. These findings together support the usefulness of minocycline as a potential treatment for cognitive impairment associated with MDD.
