Neuroinflammation as a Therapeutic Target for Mitigating the Long-Term Consequences of Acute Organophosphate Intoxication.
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ABSTRACT:
SUBMITTER: Andrew PM
PROVIDER: S-EPMC8153682 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nerve agents and some pesticides such as diisopropylfluorophosphate (DFP) cause neurotoxic manifestations that include seizures and status epilepticus (SE), which are potentially lethal and carry long-term neurological morbidity. Current antidotes for organophosphate (OP) intoxication include atropine, 2-PAM and diazepam (a benzodiazepine for treating seizures and SE). There is some evidence for partial or complete loss of diazepam anticonvulsant efficacy when given 30?min or later after exposure to an OP; this condition is known as refractory SE. Effective therapies for OP-induced SE are lacking and it is unclear why current therapies do not work. In this study, we investigated the time-dependent efficacy of diazepam in the nerve agent surrogate DFP model of OP intoxication on seizure suppression and neuroprotection in rats, following an early and late therapy. Diazepam (5?mg/kg, IM) controlled seizures when given 10?min after DFP exposure ("early"), but it was completely ineffective at 60 or 120?min ("late") after DFP. DFP-induced neuronal injury, neuroinflammation, and neurodegeneration of principal cells and GABAergic interneurons were significantly reduced by early but not late therapy. These findings demonstrate that diazepam failed to control seizures, SE and neuronal injury when given 60?min or later after DFP exposure, confirming the benzodiazepine-refractory SE and brain damage after OP intoxication. In addition, this study indicates that degeneration of inhibitory interneurons and inflammatory glial activation are potential mechanisms underlying these morbid outcomes of OP intoxication. Therefore, novel anticonvulsant and neuroprotectant antidotes, superior to benzodiazepines, are desperately needed for controlling nerve agent-induced SE and brain injury.
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Project description:Pediatric traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality in children. Experimental and clinical studies demonstrate that the developmental age, the type of injury (diffuse vs. focal) and sex may play important roles in the response of the developing brain to a traumatic injury. Advancements in acute neurosurgical interventions and neurocritical care have improved and led to a decrease in mortality rates over the past decades. However, survivors are left with life-long behavioral deficits underscoring the need to better define the cellular mechanisms underlying these functional changes. A better understanding of these mechanisms some of which begin in the acute post-traumatic period may likely lead to targeted treatment strategies. Key considerations in designing pre-clinical experiments to test therapeutic strategies in pediatric TBI include the use of age-appropriate and pathologically-relevant models, functional outcomes that are tested as animals age into adolescence and beyond, sex as a biological variable and the recognition that doses and dosing strategies that have been demonstrated to be effective in animal models of adult TBI may not be effective in the developing brain. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
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Project description:The effect of blood alcohol concentration (BAC) on outcome after traumatic brain injury (TBI) is controversial. We sought to assess the independent effect of positive BAC on long-term outcome in patients with TBI treated in the intensive care unit (ICU). We performed a retrospective analysis of 405 patients with TBI, admitted to the ICU of a large urban Level 1 trauma center between January 2009 and December 2012. Outcome was six-month mortality and unfavorable neurological outcome (defined as a Glasgow Outcome Scale score of 1 [death], 2, [vegetative state], or 3 [severe disability]). Patients were categorized by admission BAC into: no BAC (0.0‰; n=99), low BAC (<2.3‰; n=140) and high BAC (?2.3‰; n=166). Logistic regression analysis, adjusting for baseline risk and severity of illness, was used to assess the independent effect of BAC on outcome (using the no BAC group as the reference). Overall six-month mortality was 25% and unfavorable outcome was 46%. Multivariate analysis showed low BAC to independently reduce risk of six-month mortality compared with no BAC (low BAC adjusted odds ratio [AOR] 0.41, 95% confidence interval [CI] 0.19-0.88, p=0.021) and high BAC (AOR 0.58, 95% CI 0.29-1.15, p=0.120). Furthermore, a trend towards reduced risk of six-month unfavorable neurological outcome for patients with positive BAC, compared to patients with negative BAC, was noted, although this did not reach statistical significance (low BAC AOR 0.65, 95% CI 0.34-1.22, p=0.178, and high BAC AOR 0.59, 95% CI 0.32-1.09, p=0.089). In conclusion, low admission BAC (<2.3‰) was found to independently reduce risk of six-month mortality for patients with TBI, and a trend towards improved long-term neurological outcome was found for BAC-positive patients. The role of alcohol as a neuroprotective agent warrants further studies.
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Project description:Organophosphate (OP) compounds include highly toxic chemicals widely used both as pesticides and as warfare nerve agents. Existing countermeasures are lifesaving, but do not alleviate all long-term neurological sequelae, making OP poisoning a public health concern worldwide and the search for fully efficient antidotes an urgent need. OPs cause irreversible acetylcholinesterase (AChE) inhibition, inducing the so-called cholinergic syndrome characterized by peripheral manifestations and seizures associated with permanent psychomotor deficits. Besides immediate neurotoxicity, recent data have also identified neuroinflammation and microglia activation as two processes that likely play an important, albeit poorly understood, role in the physiopathology of OP intoxication and its long-term consequences. To gain insight into the response of microglia to OP poisoning, we used a previously described model of diisopropylfluorophosphate (DFP) intoxication of zebrafish larvae. This model reproduces almost all the defects seen in poisoned humans and preclinical models, including AChE inhibition, neuronal epileptiform hyperexcitation, and increased neuronal death. Here, we investigated in vivo the consequences of acute DFP exposure on microglia morphology and behaviour, and on the expression of a set of pro- and anti-inflammatory cytokines. We also used a genetic method of microglial ablation to evaluate the role in the OP-induced neuropathology. We first showed that DFP intoxication rapidly induced deep microglial phenotypic remodelling resembling that seen in M1-type activated macrophages and characterized by an amoeboid morphology, reduced branching, and increased mobility. DFP intoxication also caused massive expression of genes encoding pro-inflammatory cytokines Il1β, Tnfα, Il8, and to a lesser extent, immuno-modulatory cytokine Il4, suggesting complex microglial reprogramming that included neuroinflammatory activities. Finally, microglia-depleted larvae were instrumental in showing that microglia were major actors in DFP-induced neuroinflammation and, more importantly, that OP-induced neuronal hyperactivation was markedly reduced in larvae fully devoid of microglia. DFP poisoning rapidly triggered massive microglia-mediated neuroinflammation, probably as a result of DFP-induced neuronal hyperexcitation, which in turn further exacerbated neuronal activation. Microglia are thus a relevant therapeutic target, and identifying substances reducing microglial activation could add efficacy to existing OP antidote cocktails.
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Project description:Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.
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Project description:Cerebral malaria is an important cause of mortality and neurodisability in endemic regions. We show magnetic resonance imaging (MRI) features suggestive of cytotoxic and vasogenic cerebral edema followed by microhemorrhages in 2 adult UK cases, comparing them with an Indian cohort. Long-term follow-up images correlate ongoing changes with residual functional impairment.
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Project description:Acute intoxication with organophosphorus cholinesterase inhibitors (OPs) can trigger seizures that rapidly progress to life-threatening status epilepticus. Diazepam, long considered the standard of care for treating OP-induced seizures, is being replaced by midazolam. Whether midazolam is more effective than diazepam in mitigating the persistent effects of acute OP intoxication has not been rigorously evaluated. We compared the efficacy of diazepam vs. midazolam in preventing persistent neuropathology in adult male Sprague-Dawley rats acutely intoxicated with the OP diisopropylfluorophosphate (DFP). Subjects were administered pyridostigmine bromide (0.1 mg/kg, i.p.) 30 min prior to injection with DFP (4 mg/kg, s.c.) or vehicle (saline) followed 1 min later by atropine sulfate (2 mg/kg, i.m.) and pralidoxime (25 mg/kg, i.m.), and 40 min later by diazepam (5 mg/kg, i.p.), midazolam (0.73 mg/kg, i.m.), or vehicle. At 3 and 6 months post-exposure, neurodegeneration, reactive astrogliosis, microglial activation, and oxidative stress were assessed in multiple brain regions using quantitative immunohistochemistry. Brain mineralization was evaluated by in vivo micro-computed tomography (micro-CT). Acute DFP intoxication caused persistent neurodegeneration, neuroinflammation, and brain mineralization. Midazolam transiently mitigated neurodegeneration, and both benzodiazepines partially protected against reactive astrogliosis in a brain region-specific manner. Neither benzodiazepine attenuated microglial activation or brain mineralization. These findings indicate that neither benzodiazepine effectively protects against persistent neuropathological changes, and suggest that midazolam is not significantly better than diazepam. Overall, this study highlights the need for improved neuroprotective strategies for treating humans in the event of a chemical emergency involving OPs.
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Project description:The long-term renal consequences of kidney donation by a living donor are attracting increased appropriate interest. The overall evidence suggests that living kidney donors have survival similar to that of nondonors and that their risk of end-stage renal disease (ESRD) is not increased. Previous studies have included relatively small numbers of donors and a brief follow-up period.We ascertained the vital status and lifetime risk of ESRD in 3698 kidney donors who donated kidneys during the period from 1963 through 2007; from 2003 through 2007, we also measured the glomerular filtration rate (GFR) and urinary albumin excretion and assessed the prevalence of hypertension, general health status, and quality of life in 255 donors.The survival of kidney donors was similar to that of controls who were matched for age, sex, and race or ethnic group. ESRD developed in 11 donors, a rate of 180 cases per million persons per year, as compared with a rate of 268 per million per year in the general population. At a mean (+/-SD) of 12.2+/-9.2 years after donation, 85.5% of the subgroup of 255 donors had a GFR of 60 ml per minute per 1.73 m(2) of body-surface area or higher, 32.1% had hypertension, and 12.7% had albuminuria. Older age and higher body-mass index, but not a longer time since donation, were associated with both a GFR that was lower than 60 ml per minute per 1.73 m(2) and hypertension. A longer time since donation, however, was independently associated with albuminuria. Most donors had quality-of-life scores that were better than population norms, and the prevalence of coexisting conditions was similar to that among controls from the National Health and Nutrition Examination Survey (NHANES) who were matched for age, sex, race or ethnic group, and body-mass index.Survival and the risk of ESRD in carefully screened kidney donors appear to be similar to those in the general population. Most donors who were studied had a preserved GFR, normal albumin excretion, and an excellent quality of life.
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Project description:Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.
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Project description:Systemic lipopolysaccharide (LPS) induces an acute inflammatory response in the central nervous system (CNS) ("neuroinflammation") characterized by altered functions of microglial cells, the major resident immune cells of the CNS, and an increased inflammatory profile that can result in long-term neuronal cell damage and severe behavioral and cognitive consequences. Curcumin, a natural compound, exerts CNS anti-inflammatory and neuroprotective functions mainly after chronic treatment. However, its effect after acute treatment has not been well investigated. In the present study, we provide evidence that 50 mg/kg of curcumin, orally administered for 2 consecutive days before a single intraperitoneal injection of a high dose of LPS (5 mg/kg) in young adult mice prevents the CNS immune response. Curcumin, able to enter brain tissue in biologically relevant concentrations, reduced acute and transient microglia activation, pro-inflammatory mediator production, and the behavioral symptoms of sickness. In addition, short-term treatment with curcumin, administered at the time of LPS challenge, anticipated the recovery from memory impairments observed 1 month after the inflammatory stimulus, when mice had completely recovered from the acute neuroinflammation. Together, these results suggest that the preventive effect of curcumin in inhibiting the acute effects of neuroinflammation could be of value in reducing the long-term consequences of brain inflammation, including cognitive deficits such as memory dysfunction.
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