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Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.

ABSTRACT: BACKGROUND:Traumatic brain injury (TBI) is a critical public health and socio-economic problem worldwide. A growing body of evidence supports the involvement of inflammatory events in TBI. It has been reported that resident microglia and infiltrating monocytes promote an inflammatory reaction that leads to neuronal death and eventually behavioral and cognitive impairment. Currently, there is no effective treatment for TBI and the development of new therapeutic strategies is a scientific goal of highest priority. Laquinimod, an orally administered neuroimmunomodulator initially developed for the treatment of multiple sclerosis, might be a promising neuroprotective therapy for TBI. Herein, we aim to investigate the hypothesis that laquinimod will reduce the central nervous system (CNS) damage caused by TBI. METHODS:To test our hypothesis, Ccr2rfp/+ Cx3cr1 gfp/+ mice were submitted to a moderate TBI induced by fluid percussion. Sham controls were submitted only to craniotomy. Mice were treated daily by oral gavage with laquinimod (25 mg/kg) 7 days before and 3 days after TBI. The brains of mice treated or not treated with laquinimod were collected at 3 and 120 days post injury, and brain morphological changes, axonal injury, and neurogenesis were evaluated by microscopy analysis. We also isolated microglia from infiltrating monocytes, and the expression of immune gene mRNAs were analyzed by employing a quantitative NanoString nCounter technique. RESULTS:Laquinimod prevented ventricle enlargement caused by TBI in the long term. Immunohistochemical analyses revealed decreased axonal damage and restored neurogenesis in the laquinimod-treated TBI group at early stage (3 days post injury). Notably, laquinimod inhibited the monocytes infiltration to the brain. Hierarchial clustering demonstrated that the microglial gene expression from the TBI group treated with laquinimod resembles the sham group more than the TBI-water control group. CONCLUSIONS:Administration of laquinimod reduced lesion volume and axonal damage and restored neurogenesis after TBI. Laquinimod might be a potential therapy strategy to improve TBI long-term prognosis.

SUBMITTER: Katsumoto A

PROVIDER: S-EPMC5791334 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.

Katsumoto Atsuko A Miranda Aline S AS Butovsky Oleg O Teixeira Antônio L AL Ransohoff Richard M RM Lamb Bruce T BT

Journal of neuroinflammation 20180130 1

<h4>Background</h4>Traumatic brain injury (TBI) is a critical public health and socio-economic problem worldwide. A growing body of evidence supports the involvement of inflammatory events in TBI. It has been reported that resident microglia and infiltrating monocytes promote an inflammatory reaction that leads to neuronal death and eventually behavioral and cognitive impairment. Currently, there is no effective treatment for TBI and the development of new therapeutic strategies is a scientific ...[more]

PMID: 29382353

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Project description:IMPORTANCE:Traumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI. OBJECTIVES:To review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI. EVIDENCE REVIEW:We searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords: traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection, and clinical trials. Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review. FINDINGS:Traumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed. CONCLUSIONS AND RELEVANCE:The mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients.

Project description:Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1? interacting with its receptors, and transforming growth factor-? signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.

Project description:Traumatic brain injury induces potent inflammatory responses that can exacerbate secondary blood-brain barrier (BBB) disruption, neuronal injury, and neurological dysfunction. Dexmedetomidine is a novel α2-adrenergic receptor agonist that exert protective effects in various central nervous system diseases. The present study was designed to investigate the neuroprotective action of dexmedetomidine in a mouse traumatic brain injury model, and to explore the possible mechanisms. Adult male C57BL/6J mice were subjected to controlled cortical impact. After injury, animals received 3 days of consecutive dexmedetomidine therapy (25 µg/kg per day). The modified neurological severity score was used to assess neurological deficits. The rotarod test was used to evaluate accurate motor coordination and balance. Immunofluorescence was used to determine expression of ionized calcium binding adapter molecule-1, myeloperoxidase, and zonula occluden-1 at the injury site. An enzyme linked immunosorbent assay was used to measure the concentration of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6. The dry-wet weight method was used to measure brain water content. The Evans blue dye extravasation assay was used to measure BBB disruption. Western blot assay was used to measure protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1 p20, IL-1β, nuclear factor kappa B (NF-κB) p65, occluding, and zonula occluden-1. Flow cytometry was used to measure cellular apoptosis. Results showed that dexmedetomidine treatment attenuated early neurological dysfunction and brain edema. Further, dexmedetomidine attenuated post-traumatic inflammation, up-regulated tight junction protein expression, and reduced secondary BBB damage and apoptosis. These protective effects were accompanied by down-regulation of the NF-κB and NLRP3 inflammasome pathways. These findings suggest that dexmedetomidine exhibits neuroprotective effects against acute (3 days) post-traumatic inflammatory responses, potentially via suppression of NF-κB and NLRP3 inflammasome activation.

Project description:Our previous study has shown that the transcription factor Krüppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2'-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018.

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Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.

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Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.

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