Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy

Victor, Tanya R.; Tsirka, Stella E.

doi:10.20517/2347-8659.2020.02

Cited by 18 publications

(21 citation statements)

References 147 publications

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“…In other terms, the duration of microglial response (i.e., transitory vs. chronic) is the distinguishing feature of microglial function [ 60 ]. An aberrant pruning process has also been observed in the development of psychiatric [ 61 ] and metabolic disorders [ 62 ]. The effects depicted so far, i.e., cell shape remodeling, migration reduction, and the stimulation of phagocytosis, are known to depend on the cytoskeletal rearrangement, which plays a crucial role in the maintenance of the cellular structure and for the determination of cell motility [ 63 ] and the process of phagocytosis [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Grieco

Caris

Maggi

et al. 2021

IJMS

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The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

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Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Grieco

Caris

Maggi

et al. 2021

IJMS

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“…The HMGB1/RAGE/TLR4 signalling pathway is a key player in a number of neurological disorders that do not result in seizures; however, it has been hypothesized that the presence of extracellular HMGB1 contributes to selective vulnerability of neuronal subpopulations (e.g., pyramidal and granule cell neurons) to hyperexcitability and synaptic dysfunction within the inflammatory environment, further augmenting seizure activity [ 48 , 51 ]. Active secretion of HMGB1 from localised activated microglia and astrocytes readily increase the pool of this key DAMP [ 18 ], thereby creating neurotoxic feedback loop driving downstream ictogenic effects such as modulating synaptic plasticity, increasing blood brain barrier permeability and enhancing mossy fibre spouting [ 52 ]. This pathophysiological cascade further increases pro-inflammatory cytokine production and OS, priming the epileptogenic environment for initial and successive seizure activity.…”

Section: Role Of Os In Neuroinflammation and Epilepsymentioning

confidence: 99%

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

et al. 2022

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One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability—the hallmark of epilepsy—is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established.

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“…These cytokines stimulate aberrant neurogenesis with newborn granule cells located ectopically in the hilus of the dentate gyrus. [58][59][60] These cells may create dysfunctional connections resulting in a cognitive dysfunction. Further, the neuroinflammation may also disrupt the blood-brain barrier contributing to the edema.…”

Section: Other Mechanismsmentioning

confidence: 99%

Hippocampal volume and memory impairment after electroconvulsive therapy in patients with depression

Gbyl

Støttrup

Raghava

et al. 2021

Acta Psychiatr Scand

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Objective: Patients hesitate to consent to electroconvulsive therapy (ECT) because of the fear of memory impairment. The mechanisms underlying this impairment are unclear, but several observations suggest hippocampal alterations may be involved. We investigated whether ECT-induced change in hippocampal volume correlates with memory impairment. Methods: Using a 3 T MRI scanner, we acquired brain images and assessed cognitive performance in 22 severely depressed patients at three time points: (1) before ECT series, (2) within one week after the series, and (3) at six-month follow-up. The hippocampus was segmented into subregions using FreeSurfer. The dentate gyri (DG) were the primary regions of interest (ROIs) and major hippocampal subregions secondary ROIs. Cognitive performance was assessed using the Screen for Cognitive Impairment in Psychiatry and verbal memory using the Verbal Learning subtest. The linear mixed model and the repeated-measures correlation were used for statistical analyses. Results: ECT induced an increase in the right and left DG volume with co-occurring worsening in verbal memory, and these changes were within-patients negatively correlated (right DG, r rm = −0.85, df = 18, p = 0.0000002; left DG, r rm = −0.58, df = 18, p = 0.008). At a six-month follow-up, the volume of both DG decreased with a co-occurring improvement in verbal memory, and these changes were negatively correlated in the right DG (r rm = −0.64, df = 15, p = 0.005). Volume increases in 14 secondary ROIs were also negatively correlated with memory impairment. Conclusion: ECT-related transient increases in the volume of major hippocampal subregions within-patients are associated with memory impairment. Hippocampal alterations following ECT should be the focus in searching for causes of the cognitive side effects.

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Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy

Cited by 18 publications

References 147 publications

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

Hippocampal volume and memory impairment after electroconvulsive therapy in patients with depression

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