Examining other emergency response teams' methods of adaptation, communication, problem solving, trust building, and developing shared knowledge among team members can improve cybersecurity incident response teams' performance.
The subjective experience of AR can play an important role in determining risk for detrimental physical health outcomes, particularly CVD risk.
GLP-1 agonists have become increasingly interesting as a new Parkinson’s disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. “Motivated” behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.
This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson's disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.Int. J. Mol. Sci. 2019, 20, 6251 2 of 17 in nigral neurons in aged humans with sharp elevations starting shortly before age 70. This correlates with age being a known major risk factor for PD. A better understanding of the progressive cellular events that precede the appearance of behavioral symptoms will be critical for the early diagnosis of PD and development of more effective treatment strategies.It has been suggested that gender is an important factor in the development of PD. The disease is more common in men than in woman by an approximate ratio of 1.5-2:1 [18,19]. In addition to prevalence, several other PD-coupled parameters differ between men and women, including onset of symptoms, types of motor and non-motor symptoms, medication use, the effect size of PD risk factors, levodopa bioavailability, neuropsychiatric, and cognitive changes, development of hallucinations, caregiver utilization and reliance, and the quality of life [20,21]. In women, the age of PD onset has shown a positive correlation with fertility. Sex hormones, especially estrogen, may thus influence PD pathogenesis and be an important gender differentiation factor [22,23]. Here we use the MitoPark (MP) mouse model of PD where the mitochondrial transcription factor, TFAM, is specifically deleted in midbrain dopamine (DA) neurons. There is subsequent progressive degeneration of midbrain DA neurons which project to both striatum and extrastriatal telencephalic sites. Since the TFAM deletion is driven by the DAT promoter, neurons that do not express DAT are spared. Ovariectomy was used to address gender differences and the possible protective effects of estrogen on the time course of degeneration of DA neurons. ResultsDA release rate was measured by fast scan cyclic voltammetry (FSCV) in ex vivo (in vitro) brain slices. The capacity of axon terminals to release DA was assessed by using one single pulse (for tonic) or 10 pulses (for phasic) stimulation delivered at 25 Hz under 10 volts stimulation intensities....
The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery. Next, we investigated the number and morphological characteristic of peri-infarct microglia at different time points and elucidated the mechanism of microglial response by VPA treatment. Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 min, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 min after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 h after reperfusion, and neurological symptoms were evaluated. VPA didn’t significantly reduce infarct volume but did ameliorate neurological deficit at least partially compared with vehicle. Meanwhile, VPA reduced dMCAo-induced elevation of IL-6 at 24 h post-stroke and significantly decreased the number of CD11b-positive microglia within peri-infarct cortex at 7 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions, smaller soma size and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 and 7 days, suggesting that VPA has core effects on microglial morphology. The modulation of microglia morphology caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Furthermore, qPCR analysis of CD11b-positive cells at 3 days post-stroke suggested that VPA could partially enhance M2 subset polarization of microglia in peri-infarct cortex. Analysis of VPA-induced changes to gene expressions at 3 days post-stroke implies that these alternations of the biomarkers and microglial responses are implicated in the upregulation of wound healing, collagen trimmer, and extracellular matrix genes within peri-infarct cortex. Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the morphological characteristics and transcriptional profiles of microglia and extracellular matrix remodeling, which could contribute to the improved recovery.
During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH.
To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson’s disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.
Background: Recently, microglia, being the determinant of environment in peri-infarct tissue and strongly influence the potential for neuronal plasticity, has been implicated in post-ischemic secondary injury and functional recovery. However, the specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. These effects are usually attributed, at least partially, to the anti-inflammatory ability of this drug to suppress microglial activation. In this study, we explored whether a low dose of VPA after stroke could modify reactive responses in microglia/macrophages and optimize peri-infarct microenvironments to improve functional recovery.Methods: Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 minutes, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 minutes after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 hours after reperfusion, and neurological symptoms were evaluated through 48 hours thereafter. The production of cytokines and biomarkers after insult was determined using enzyme-linked immunosorbent assays (ELISAs) and western blot. The effects of VPA on the activation of peri-infarct CD11b-positive cells were assessed based on cellular density and quality observation of morphology with fractal analysis and circularity index. The expressions of genes within peri-infarct zones at 3 days were determined by RNA-sequencing analysis. To determine whether VPA modulates microglial polarization, gentleMACS Dissociator was used to isolate CD11b-positive cells from the peri-infarct cortex of rats treated with or without VPA 3 days after dMCAo, after which the cells were subjected to qPCR analysis.Results: 200 mg/kg of VPA injected 90 minutes after ischemia induction did not significantly reduce infarct volume but did improve neurological deficit at least partially compared with vehicle. Meanwhile, VPA significantly reduced dMCAo-induced elevation of IL-6 at 24 hours post-stroke and significantly decreased the number of CD11b-positive microglia/macrophages within peri-infarct cortex at 7 but not at 2 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 days and 7 days, suggesting that VPA has core effects on microglial activation. The attenuation of microglia/macrophage activation caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Analysis of VPA-induced changes to gene expressions in the peri-infarct cortex at 3 days post-stroke indicated the upregulation of wound healing, collagen trimmer, and extracellular matrix genes. Furthermore, qPCR analysis of CD11b-positive cells suggested that VPA could partially enhance M2 subset polarization of microglia/macrophages in peri-infarct cortex.Conclusions: Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the extracellular matrix remodeling and morphological characteristics and transcriptional profiles of microglia/macrophages, which could contribute to the improved recovery.
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