Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury

Lloyd, Elisabeth A.; Somera-Molina, Kathleen; Eldik, Linda J. Van; Watterson, D. Martin; Wainwright, Mark S.

doi:10.1186/1742-2094-5-28

Cited by 161 publications

(135 citation statements)

References 63 publications

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“…To determine whether the effects of TBI on seizure susceptibility were linked to activation of astrocytes or microglia, we measured changes in GFAP, S100B, and the microglial protein Iba1, and treated mice following TBI with the CNS-penetrant small molecule Minozac (Mzc). As we have previously reported, Mzc treatment suppresses proinflammatory cytokine upregulation resulting from TBI (Lloyd et al, 2008), or kainic acid-induced seizures (Somera-Molina et al, 2009).…”

mentioning

confidence: 56%

“…Mice were subjected to closed-skull traumatic brain injury using a stereotactically guided pneumatic compression device with minor modification of published methods as previously described (Lloyd et al, 2008). Briefly, the mice were anesthetized with isoflurane (4% induction, 1.5% maintenance) in 100% oxygen.…”

Section: Mouse Model Of Closed Head Injurymentioning

confidence: 99%

“…In the present studies, we used a mouse closed-skull TBI model (Lloyd et al, 2008;Wang et al, 2007) to test the hypothesis that TBI results in increased susceptibility to seizures, and that this enhanced response to a seizure-inducing ''second-hit'' is due to an increase in activated astrocytes and microglia. To quantify changes in seizure threshold produced by TBI, and to deliver a controlled second-hit, we allowed mice to recover for 7 days before administering an electroconvulsive shock (ECS), a well-established method for seizure induction in the rodent (Ferraro et al, 2002;Frankel et al, 2001).…”

mentioning

confidence: 99%

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Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

Chrzaszcz

Venkatesan

Dragisic

et al. 2010

Journal of Neurotrauma

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The mechanisms linking traumatic brain injury (TBI) to post-traumatic epilepsy (PTE) are not known and no therapy for prevention of PTE is available. We used a mouse closed-skull midline impact model to test the hypotheses that TBI increases susceptibility to seizures in a ''two-hit'' injury model, and that suppression of cytokine upregulation after the first hit will attenuate the increased susceptibility to the second neurological insult. Adult male CD-1 mice underwent midline closed skull pneumatic impact. At 3 and 6 h after impact or sham procedure, the mice were injected IP with either Minozac (Mzc), a suppressor of proinflammatory cytokine upregulation, or vehicle (saline). On day 7 after sham operation or TBI, seizures were induced using electroconvulsive shock (ECS), and susceptibility to seizures was measured by the current required for seizure induction. Activation of glia, neuronal injury, and metallothionein-immunoreactive cells were quantified in the hippocampus by immunohistochemical methods. Neurobehavioral function over 14-day recovery was quantified using the Barnes maze. Following TBI there was a significant increase in susceptibility to seizures induced by ECS, and this susceptibility was prevented by suppression of cytokine upregulation with Mzc. Astrocyte activation, metallothionein expression, and neurobehavioral impairment were also increased in the two-hit group subjected to combined TBI and ECS. These enhanced responses in the two-hit group were also prevented by suppression of proinflammatory cytokine upregulation with Mzc. These data implicate glial activation in the mechanisms of epileptogenesis after TBI, and identify a potential therapeutic approach to attenuate the delayed neurological sequelae of TBI.

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mentioning

confidence: 56%

Section: Mouse Model Of Closed Head Injurymentioning

confidence: 99%

mentioning

confidence: 99%

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Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

Chrzaszcz

Venkatesan

Dragisic

et al. 2010

Journal of Neurotrauma

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“…For example, IL-1 beta neutralizing antibody (IgG2a/k) (Clausen et al, 2009), dexanabinol (HU-211, an inhibitor of TNF-alpha at a post-transcriptional stage, (Shohami et al, 1997), antioxidants (Trembovler et al, 1999), Minozac and a synthetic analog of tripeptide glypromate (NNZ-2566, inhibitors of glial activation and pro-inflammatory cytokines, (Lloyd et al, 2008;Wei et al, 2009), and simvastatin, an inhibitor of activation of astrocytes and a cholesterol lowering drug (Wu et al, 2009), all provided protection by reduction of neuronal loss and neurological deficits.…”

Section: Increased Inflammation In Penetrating Tbimentioning

confidence: 99%

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

Prasad¹,

Bondy

2015

Brain Research

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AnxietyPsychological damage a b s t r a c t Post-traumatic stress disorder (PTSD) is a complex mental disorder with psychological and emotional components, caused by exposure to single or repeated extreme traumatic events found in war, terrorist attacks, natural or man-caused disasters, and by violent personal assaults and accidents. Mild traumatic brain injury (TBI) occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck as in contact sports, or when in close proximity to a blast pressure wave following detonation of explosives in the battlefield. Penetrating TBI occurs when an object penetrates the skull and damages the brain, and is caused by vehicle crashes, gunshot wound to the head, and exposure to solid fragments in the proximity of explosions, and other combat-related head injuries. Despite clinical studies and improved understanding of the mechanisms of cellular damage, prevention and treatment strategies for patients with PTSD and TBI remain unsatisfactory. To develop an improved plan for treating and impeding progression of PTSD and TBI, it is important to identify underlying biochemical changes that may play key role in the initiation and progression of these disorders. This review identifies three common biochemical events, namely oxidative stress, chronic inflammation and excitotoxicity that participate in the initiation and progression of these conditions. While these features are separately discussed, in many instances, they overlap. This review also addresses the goal of developing novel treatments and drug regimens, aimed at combating this triad of events common to, and underlying, injury to the brain.

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“…This treatment also prevented the ensuing cognitive dysfunctions seen in mice exposed to TBI and experiencing seizures. Treatment with minozac after SE in PN15 rats reversed the enhanced seizure susceptibility to KA; this drug decreased microglia activation and proinflammatory cytokines in hippocampus [156]. …”

Section: Immunity and Anti-inflammatory Therapies In Epilepsymentioning

confidence: 99%

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

Líu²,

Qin³

2013

Current Neuropharmacology

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Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE.

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Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury

Cited by 161 publications

References 63 publications

Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

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