Models of Parkinson's disease (PD) based on selective neuronal death have been used to study pathogenic mechanisms underlying nigral cell death and in some instances to develop symptomatic therapies. For validation of putative neuroprotectants, a model is desirable in which the events leading to neurodegeneration replicate those occurring in the disease. We developed a human in vitro model of PD based on the assumption that dysregulated cytoplasmic dopamine levels trigger cell loss in this disorder. Differentiated human mesencephalic neuron-derived cells were exposed to methamphetamine (METH) to promote cytoplasmic dopamine accumulation. In the presence of elevated iron concentrations, as observed in PD, increased cytosolic dopamine led to oxidative stress, c-Jun N-terminal kinase (JNK) pathway activation, neurite degeneration, and eventually apoptosis. We examined the role of the mixed-lineage kinases (MLKs) in this complex degenerative cascade by using the potent inhibitor 3,9 -bis[(ethylthio)methyl]-K-252a (CEP1347). Inhibition of MLKs not only prevented FeCl2ϩ /METH-induced JNK activation and apoptosis but also early events such as neurite degeneration and oxidative stress. This broad neuroprotective action of CEP1347 was associated with increased expression of an oxidative stress-response modulator, activating transcription factor 4. As a functional consequence, transcription of the cystine/glutamate and glycine transporters, cellular cystine uptake and intracellular levels of the redox buffer glutathione were augmented. In conclusion, this new human model of parkinsonian neurodegeneration has the potential to yield new insights into neurorestorative therapeutics and suggests that enhancement of cytoprotective mechanisms, in addition to blockade of apoptosis, may be essential for disease modulation.

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Gestational disruption of neurodevelopment has been proposed to lead to pathophysiological changes similar to those underlying schizophrenia. We induced such disruption by treating pregnant rat dams with methylazoxymethanol acetate (MAM) on gestational day 17 (GD17). Total brain size and that of the prefrontal cortex and hippocampus were reduced in adult rats exposed prenatally to MAM. When locomotor activity was assessed in an open field, MAM-exposed rats were hyper-responsive to a mild stress and to amphetamine (2 mg/kg, s.c.). They also engaged in less social interaction than controls. We studied, by microdialysis, the effect of amphetamine on extracellular dopamine in the nucleus accumbens and the medial prefrontal cortex of freely moving control and MAM-exposed rats. Amphetamine (2 mg/kg, s.c.) induced an increase in dopamine release that was larger in the nucleus accumbens of MAM-exposed rats than in controls, whereas no difference was seen in the medial prefrontal cortex. In controls, amphetamine infused into the medial prefrontal cortex (50 mM) led to a slight decrease in extracellular dopamine in the nucleus accumbens. This effect was absent in MAMexposed rats, where a transient increase in nucleus accumbens dopamine levels was seen after amphetamine infusion. These results show that the late gestational disruption of neurogenesis in the rat leads to behavioral changes that mimic positive and negative schizophrenia symptoms, and also to a dysregulation of subcortical dopamine neurotransmission. This study contributes to the evaluation of the validity of the prenatal MAM GD17 treatment in rats as an animal model for schizophrenia.

Background Current clinical assessments of people with multiple sclerosis are episodic and may miss critical features of functional fluctuations between visits. Objective The goal of the research was to assess the feasibility of remote active testing and passive monitoring using smartphones and smartwatch technology in people with multiple sclerosis with respect to adherence and satisfaction with the FLOODLIGHT test battery. Methods People with multiple sclerosis (aged 20 to 57 years; Expanded Disability Status Scale 0-5.5; n=76) and healthy controls (n=25) performed the FLOODLIGHT test battery, comprising active tests (daily, weekly, every two weeks, or on demand) and passive monitoring (sensor-based gait and mobility) for 24 weeks using a smartphone and smartwatch. The primary analysis assessed adherence (proportion of weeks with at least 3 days of completed testing and 4 hours per day passive monitoring) and questionnaire-based satisfaction. In-clinic assessments (clinical and magnetic resonance imaging) were performed. Results People with multiple sclerosis showed 70% (16.68/24 weeks) adherence to active tests and 79% (18.89/24 weeks) to passive monitoring; satisfaction score was on average 73.7 out of 100. Neither adherence nor satisfaction was associated with specific population characteristics. Test-battery assessments had an at least acceptable impact on daily activities in over 80% (61/72) of people with multiple sclerosis. Conclusions People with multiple sclerosis were engaged and satisfied with the FLOODLIGHT test battery. FLOODLIGHT sensor-based measures may enable continuous assessment of multiple sclerosis disease in clinical trials and real-world settings. Trial Registration ClinicalTrials.gov: NCT02952911; https://clinicaltrials.gov/ct2/show/NCT02952911

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Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P < 0.05), polymorphomonuclear cell infiltration (P < 0.05), and white matter damage (P < 0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P < 0.01 and P < 0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.

Background: Sensor-based monitoring tools fill a critical gap in multiple sclerosis (MS) research and clinical care. Objective: The aim of this study is to assess performance characteristics of the Floodlight Proof-of-Concept (PoC) app. Methods: In a 24-week study (clinicaltrials.gov: NCT02952911), smartphone-based active tests and passive monitoring assessed cognition (electronic Symbol Digit Modalities Test), upper extremity function (Pinching Test, Draw a Shape Test), and gait and balance (Static Balance Test, U-Turn Test, Walk Test, Passive Monitoring). Intraclass correlation coefficients (ICCs) and age- or sex-adjusted Spearman’s rank correlation determined test–retest reliability and correlations with clinical and magnetic resonance imaging (MRI) outcome measures, respectively. Results: Seventy-six people with MS (PwMS) and 25 healthy controls were enrolled. In PwMS, ICCs were moderate-to-good (ICC(2,1) = 0.61–0.85) across tests. Correlations with domain-specific standard clinical disability measures were significant for all tests in the cognitive ( r = 0.82, p < 0.001), upper extremity function (|r|= 0.40–0.64, all p < 0.001), and gait and balance domains ( r = −0.25 to −0.52, all p < 0.05; except for Static Balance Test: r = −0.20, p > 0.05). Most tests also correlated with Expanded Disability Status Scale, 29-item Multiple Sclerosis Impact Scale items or subscales, and/or normalized brain volume. Conclusion: The Floodlight PoC app captures reliable and clinically relevant measures of functional impairment in MS, supporting its potential use in clinical research and practice.

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