A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Gao, Chuang; Yu, Qian; Huang, Jinhao; Wang, Dong; Su, Wanqiang; Wang, Peng; Guo, Linyue; Quan, Wei; An, Shuo; Zhang, Jianning; Jiang, Rongcai

doi:10.1007/s12035-016-0318-0

Cited by 72 publications

(58 citation statements)

References 53 publications

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“…Anti-inflammatory Treg T cells and M2-type microglia and IL-10 were increased by more than twofold by fingolimod. 266 These results support the antiepileptogenic and disease-modifying effects of fingolimod in animal models of SE. Investigations in additional models of acute brain injury (ie, TBI/PTE, CNS infection, stroke) are needed, as are studies of the best therapeutic window for drug intervention to maximize the drug's therapeutic effects.…”

Section: Fingolimodsupporting

confidence: 58%

“…These effects were associated with twofold reduction in axonal damage, brain edema and microglia activation, normalization in the cortical levels of several inflammatory molecules, and prevention of T‐cell brain extravasation assessed in the injured cortex. Anti‐inflammatory Treg T cells and M2‐type microglia and IL‐10 were increased by more than twofold by fingolimod …”

Section: Fingolimodmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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Section: Fingolimodsupporting

confidence: 58%

Section: Fingolimodmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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“…Immunomodulatory agents, including fingolimod, thymosin b4, peroxisome proliferator-activated receptors agonists (such as rosiglitazone and pioglitazone), the IL-1 receptor antagonist and cell cycle inhibitor flavopiridol have been confirmed to inhibit the inflammatory response after TBI, through inhibiting overactivation of microglia or promoting M2 polarization. However, all of these drugs are in preclinical studies (15,16,18). Consequently, it is important to further explore new strategies for alleviating the inflammatory response in the brain after TBI.…”

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confidence: 99%

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

et al. 2017

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Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neuronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro. The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR-124-3p increased most apparently in the miRNAs. We found that miR-124-3p promoted the anti-inflamed M2 polarization in microglia, and microglial exosomal miR-124-3p inhibited neuronal inflammation in scratch-injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR-124-3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR-124-3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR-124-3p by pathway analysis. We proved that it was directly targeted by miR-124-3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR-124-3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR-124-3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreased expression on RhoA and neurodegenerative proteins [Ab-peptide and p-Tau]. It also improved the neurologic outcome and inhibited neuroinflammation in mice with rTBI. Taken together, increased miR-124-3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR-124-3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR-124-3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.-Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. FASEB J. 32, 512-528 (2018). www.fasebj.org

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“…Primary brain injury, which occurs immediately after trauma, can induce biochemical changes and ultimately lead to secondary neuronal cell loss (Jindal et al, 2016). The main mechanisms underlying secondary brain injury are associated with endoplasmic reticulum stress (ER stress), oxidative stress, mitochondrial dysfunction, inflammation and apoptosis (Dash et al, 2015; Gao et al, 2016; Wang et al, 2016; Yang et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

Sun

Wang

et al. 2017

Front. Cell. Neurosci.

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Traumatic brain injury (TBI) is one of the leading causes of trauma-induced mortality and disability, and emerging studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of TBI. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been reported to act as an ER stress inhibitor and chemical chaperone and to have the potential to attenuate apoptosis and inflammation. To study the effects of TUDCA on brain injury, we subjected mice to TBI with a controlled cortical impact (CCI) device. Using western blotting, we first examined TBI-induced changes in the expression levels of GRP78, an ER stress marker, p-PERK, PERK, p-eIF2a, eIF2a, ATF4, p-Akt, Akt, Pten, Bax, Bcl-2, Caspase-12 and CHOP, as well as changes in the mRNA levels of Akt, GRP78, Caspase-12 and CHOP using RT-PCR. Neuronal cell death was assessed by a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and CHOP expression in neuronal cells was detected by double-immunofluorescence staining. Neurological and motor deficits were assessed by modified neurological severity scores (mNSS) and beam balance and beam walking tests, and brain water content was also assessed. Our results indicated that ER stress peaked at 72 h after TBI and that TUDCA abolished ER stress and inhibited p-PERK, p-eIF2a, ATF4, Pten, Caspase-12 and CHOP expression levels. Moreover, our results show that TUDCA also improved neurological function and alleviated brain oedema. Additionally, TUDCA increased p-Akt expression and the Bcl-2/Bax ratio. However, the administration of the Akt inhibitor MK2206 or siRNA targeting of Akt abolished the beneficial effects of TUDCA. Taken together, our results indicate that TUDCA may attenuate early brain injury via Akt pathway activation.

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A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Cited by 72 publications

References 53 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

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