Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis

Mancini, Andrea; Tantucci, Michela; Mazzocchetti, Petra; Iure, Antonio de; Durante, Valentina; Macchioni, Lara; Giampà, Carmela; Alvino, Alessandra; Gaetani, Lorenzo; Costa, Cinzia; Tozzi, Alessandro; Calabresi, Paolo

doi:10.1016/j.nbd.2018.01.002

Cited by 29 publications

(27 citation statements)

References 56 publications

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“…Microglial activation is the major pathogenic contribution in the development of EAE through the release of proinflammatory cytokines. 39 Hence, we examined the activation of microglia in the spinal cord using IHC staining. As shown in Table 2, a notable infiltration of IL-6 + , TNF + , and Iba-1 + cells was observed in the spinal cords harvested from EAE mice, which was significantly reduced by the NHNK treatment.…”

Section: Nhnk Attenuated the Infiltration Of Activated Microglial Intmentioning

confidence: 99%

<p>Development of Nanosome-Encapsulated Honokiol for Intravenous Therapy Against Experimental Autoimmune Encephalomyelitis</p>

Hsiao¹,

Chen²,

Liang³

et al. 2020

IJN

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Background: Honokiol has been reported to possess anti-inflammatory and neuroprotective activities. However, the poor aqueous solubility of honokiol limits its clinical application for systemic administration. Purpose: This study aims to develop a novel formulation of nanosome-encapsulated honokiol (NHNK) for intravenous therapy against mouse experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis. Methods: Nanosomes and NHNK were prepared by using an ultra-high pressure homogenization (UHPH) method. Mice were treated with NHNK or empty nanosomes during the peak phase of EAE symptoms. Symptoms of EAE were monitored and samples of the spinal cord were obtained for histopathological examinations. Results: The stock of NHNK containing honokiol in the nanosome formulation, which showed the structure of single phospholipid bilayer membranes, was well formulated with the particle size of 48.0 ± 0.1 nm and the encapsulation efficiency 58.1 ± 4.2%. Intravenous administration of NHNK ameliorated the severity of EAE accompanied by a significant reduction of demyelination and inflammation in the spinal cord. Furthermore, NHNK decreased the number of IL-6 + , Iba-1 + TNF + , Iba-1 + IL-12 p40 + , and CD3 + IFN-γ + cells infiltrating the spinal cord. Conclusion: The UHPH method simplified the preparation of NHNK with uniformly distributed nanosize and high encapsulation efficiency. Intravenous administration of NHNK ameliorated the severity of EAE by suppressing the infiltration of activated microglia and Th1 cells into the spinal cord. Collectively, these results suggest that the formulation of NHNK is a prospective therapeutic approach for inflammatory CNS diseases, such as multiple sclerosis.

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Section: Nhnk Attenuated the Infiltration Of Activated Microglial Intmentioning

confidence: 99%

<p>Development of Nanosome-Encapsulated Honokiol for Intravenous Therapy Against Experimental Autoimmune Encephalomyelitis</p>

Hsiao¹,

Chen²,

Liang³

et al. 2020

IJN

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“…To investigate the role of NO and its intracellular cascade in neuronal cytolysis, the NO synthesis were added into the culture medium of neurons at 100pg/ml, 100 pg/ml, 80 ng/ml and 20 ng/ml respectively. The concentrations of inhibitors, activators and recombinant cytokines were selected based on previous studies [23,30].…”

Section: Inhibitors Activators and Recombinant Cytokinesmentioning

confidence: 99%

“…To investigate the mechanisms of cytolysis induced by conditioned media from microglias treated with OMS+NB IgG, we focus on the NO/sGC/PKG pathway, for its role in neuronal death is well documented [21][22][23] and the production of NO from microglias was raised by OMS+NB IgG (Fig. 2a2-d2).…”

Section: The Effects Of Inhibitors or Activators Of No/sgc/pkg Pathwamentioning

confidence: 99%

“…NO, synthesized and released by activated microglias, can activate sGC and PKG in neurons, leading to neuronal death by mitochondrial dysfunction [21,22] and increased neuronal susceptibility to mitochondrial dysfunction [23], similar with its function in pancreatic tissues [45]. On the other hand, exposure to NO has anti-apoptotic function through sGC and PKG in both neuronal and myocardial tissues [46,47], the opposite influences of NO intracellular signal may be caused by the way (transient or sustained) and concentration of NO, as well as cell type.…”

Section: The No/sgc/pkg Pathway Takes Part In Neuronal Cytolysis Indumentioning

confidence: 99%

“…In patients with pediatric OMS and NB, we and others have revealed that sera or IgG purified from sera causes cytolysis in cultured cerebellar and cerebral neurons [6,7]. Additionally, activated microglias can synthesize and release nitric oxide (NO), which can activate the downstream soluble guanylyl cyclase (sGC) and protein kinase G (PKG) in neurons, thus exerting neuronal death by mitochondrial dysfunction [21,22] and increased neuronal susceptibility to mitochondrial dysfunction [23]. However, whether the cytolysis of neurons can be induced by activated microglias in children with OMS and NB via the NO/sGC/PKG cascade is still unknown.Here, we found that sera or serum IgG from children with OMS and NB induces the activation of cultured cerebral cortical and cerebellar microglias, but not astrocytes.…”

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Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

Ding

Yang

et al. 2020

Preprint

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BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare neurological disease. Some children with OMS also have neuroblastoma (NB). We and others have previously documented that serum IgG from children with OMS and NB induces neuronal cytolysis via several signaling pathways. However, mechanisms underlying OMS remain unclear. Here we investigated whether nitric oxide (NO) from activated microglias and its cascade contribute to neuronal cytolysis in pediatric OMS. MethodsThe activation of cultured cerebral cortical and cerebellar microglias incubated with sera or IgG isolated from sera of children with OMS and NB was measured by the expression of the activation marker, cytokines and NO. Neuronal cytolysis was determined after exposing to IgG-treated microglia conditioned media. Using inhibitors and activators, the effects of NO synthesis and its intracellular cascade, namely soluble guanylyl cyclase (sGC) and protein kinase G (PKG), on neuronal cytolysis were evaluated. ResultsIncubation with sera or IgG from children with OMS and NB increased the activation of cerebral cortical and cerebellar microglias, but not the activation of astrocytes or the cytolysis of glial cells.Moreover, the cytolysis of neurons was elevated by conditioned media from microglias incubated with IgG from children with OMS and NB, which was relieved by the inhibitors of NO signaling. By contrast, neuronal cytolysis was exacerbated by the activators of NO signaling but not proinflammatory cytokines. Neuronal cytolysis was suppressed by pretreatment with the microglial inhibitor minocycline, a clinically tested drug. Finally, increased microglial activation did not depend on the Fab fragment of serum IgG. ConclusionsSerum IgG from children with OMS and NB potentiates microglial activation, which induces neuronal cytolysis through the NO/sGC/PKG pathway, suggesting an applicability of microglial inhibitor as a therapeutic candidate. BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare but devastating neurological disease, characterized by opsoclonus, myoclonus and ataxia. Most patients suffer from persistent deficits in cognition, neurology and behavior. Some children with OMS also have neuroblastoma (NB), although varied percentages have been reported [1][2][3][4][5]. Previously, we have documented that the insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase cascade alleviates neuronal cytolysis induced by serum IgG from children with OMS and NB [6], others also reported that the phosphorylation of extracellular signal-regulated kinase contributes to neuronal cytolysis in pediatric OMS [7]. Yet, the cellular and molecular mechanisms associated with neuronal cytolysis underlying pediatric OMS remain unclear. Microglias are major immune effectors in the central nervous system (CNS) and have an important physiological function in inflammation [8]. Notably, patients with pediatric OMS exhibit increased expression of a microglial marker and proinflammatory cytokines in cerebrospinal fluid (CSF) and some children with OMS are post-inf...

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Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

Calabrese,

Preziosa,

Scalfari

et al. 2024

Annals of Neurology

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Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving “chronic” worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion‐independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024

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Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis

Cited by 29 publications

References 56 publications

<p>Development of Nanosome-Encapsulated Honokiol for Intravenous Therapy Against Experimental Autoimmune Encephalomyelitis</p>

<p>Development of Nanosome-Encapsulated Honokiol for Intravenous Therapy Against Experimental Autoimmune Encephalomyelitis</p>

Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

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