Gamification to Improve Medication Adherence: A Mixed-method Usability Study for MedScrab.

Medication non-adherence is a prevalent healthcare problem with poor health outcomes and added healthcare costs. MedScrab, a gamification-based mHealth app, is the first attempt to deliver crucial life-saving medication information to patients and increase their medication adherence. The paper presents the development of MedScrab and a two-phase mixed-method usability evaluation of MedScrab. Phase I qualitatively evaluated MedScrab using a think-aloud protocol for its usability. With 51 participants, qualitative data analysis of Phase I revealed two themes: positive functionality of the app and four areas of improvement. The improvement recommendations were incorporated into MedScrab's design. Phase I also validated a widely used mHealth App Usability Questionnaire (MAUQ). Quantitative data analysis of Phase I reduced the original 18-item MAUQ scale to a 15-item scale with two factors: ease of use (4 items) and usefulness and satisfaction (11 items). Phase II surveyed 83 participants from Amazon's Mechanical Turk using a modified MAUQ. The modified MAUQ scale showed strong internal consistency (Cronbach alpha = 0.959) and high factor loadings (between 0.623 and 0.987). The study design of the usability evaluation can serve as a methodological guide for designing, evaluating, and improving mHealth apps.The usability study showed that MedScrab was perceived as ease of use (6.24 out of 7) with high usefulness and satisfaction (5.72 out of 7). The quantitative data analysis results support the use of the modified MAUQ as a valid instrument to measure the usability of the MedScrab. However, the instrument should be used with adaptation based on the app's characteristics.

Application of pharmacogenetics in clinical practice: problems and solutions.

This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.

A Case of Fronto-Temporal Dementia (FTD) Masquerading as Mood Disorder.

A 56-year old Chinese female was referred to an academic medical center with atypical, treatment-resistant depression that continued for approximately 3 years after her sister's death. Comprehensive evaluation including neurocognitive testing, EEG, spinal tap, HIV testing and brain MRI revealed behavioral variant of fronto-temporal dementia (bvFTD) with significant frontal and temporal lobe atrophy.This patient's unusual clinical presentation emphasizes the overlap between depression and bvFTD, and underlines the importance of prompt, accurate diagnosis to minimize often-ineffective pharmacological interventions and caregiver burnout.

Vascular depression consensus report - a critical update.

BACKGROUND: Vascular depression is regarded as a subtype of late-life depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. Although the term is commonly used in research settings, widely accepted diagnostic criteria are lacking and vascular depression is absent from formal psychiatric manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition - a fact that limits its use in clinical settings. Magnetic resonance imaging (MRI) techniques, showing a variety of cerebrovascular lesions, including extensive white matter hyperintensities, subcortical microvascular lesions, lacunes, and microinfarcts, in patients with late life depression, led to the introduction of the term "MRI-defined vascular depression". DISCUSSION: This diagnosis, based on clinical and MRI findings, suggests that vascular lesions lead to depression by disruption of frontal-subcortical-limbic networks involved in mood regulation. However, despite multiple MRI approaches to shed light on the spatiotemporal structural changes associated with late life depression, the causal relationship between brain changes, related lesions, and late life depression remains controversial. While postmortem studies of elderly persons who died from suicide revealed lacunes, small vessel, and Alzheimer-related pathologies, recent autopsy data challenged the role of these lesions in the pathogenesis of vascular depression. Current data propose that the vascular depression connotation should be reserved for depressed older patients with vascular pathology and evident cerebral involvement. Based on current knowledge, the correlations between intra vitam neuroimaging findings and their postmortem validity as well as the role of peripheral markers of vascular disease in late life depression are discussed. CONCLUSION: The multifold pathogenesis of vascular depression as a possible subtype of late life depression needs further elucidation. There is a need for correlative clinical, intra vitam structural and functional MRI as well as postmortem MRI and neuropathological studies in order to confirm the relationship between clinical symptomatology and changes in specific brain regions related to depression. To elucidate the causal relationship between regional vascular brain changes and vascular depression, animal models could be helpful. Current treatment options include a combination of vasoactive drugs and antidepressants, but the outcomes are still unsatisfying.

Platinum sensitivity and CD133 expression as risk and prognostic predictors of central nervous system metastases in patients with epithelial ovarian cancer.

BACKGROUND: To characterize prognostic and risk factors of central nervous system (CNS) metastases in patients with epithelial ovarian cancer (EOC). METHODS: A retrospective analysis of Xijing Hospital electronic medical records was conducted to identify patients with pathologically confirmed EOC and CNS metastases. In addition to patient demographics, tumor pathology, treatment regimens, and clinical outcomes, we compared putative cancer stem cell marker CD133 expression patterns in primary and metastatic lesions as well as in recurrent EOC with and without CNS metastases. RESULTS: Among 1366 patients with EOC, metastatic CNS lesions were present in 29 (2.1%) cases. CD133 expression in primary tumor was the only independent risk factor for CNS metastases; whilst the extent of surgical resection of primary EOC and platinum resistance were two independent factors significantly associated with time to CNS metastases. Absence of CD133 expression in primary tumors was significantly associated with high platinum sensitivity in both patient groups with and without CNS metastases. Platinum resistance and CD133 cluster formation in CNS metastases were associated with decreased survival, while multimodal therapy including stereotactic radiosurgery (SRS) for CNS metastases was associated with increased survival following the diagnosis of CNS metastases. CONCLUSIONS: These data suggest that there exist a positive association between CD133 expression in primary EOC, platinum resistance and the increased risk of CNS metastases, as well as a less favorable prognosis of EOC. The absence of CD133 clusters and use of multimodal therapy including SRS could improve the outcome of metastatic lesions. Further investigation is warranted to elucidate the true nature of the association between platinum sensitivity, CD133 expression, and the risk and prognosis of CNS metastases from EOC.

Opportunities to integrate nutrigenomics into clinical practice and patient counseling.

BACKGROUND: Little progress has been made in translating nutrigenomics knowledge into clinical counseling in the past decade. Currently, clinicians are overwhelmed by nutrigenomics information without the proper scientific guidelines on patient counseling. METHODS: In this study, we conducted a scoping review of the primary literature to assess the current evidence of nutrigenomics counseling. A literature search using PRISMA guidelines identified the current challenges and opportunities facing nutrigenomics counseling in clinical practice. RESULTS: We identified four main themes: inadequate training, lack of awareness, underdeveloped nutrigenomics counseling skills, and unreliable evidence-based practice information. Many clinicians did not have the necessary knowledge to perform nutrigenomic counseling and were unaware of the available scientific information source. Moreover, there are no guidelines in the scientific community to counsel patients on nutrigenomics testing. CONCLUSION: Opportunities exist for government and non-government entities to create an evidence-based information platform using clinical guidelines to integrate nutrigenomics knowledge from bench to bedside successfully.

PGxKnow: a pharmacogenomics educational HoloLens application of augmented reality and artificial intelligence.

Aim: To develop and assess an augmented reality tool for pharmacogenomics (PGx) education based on artificial intelligence. Materials & methods: A HoloLens application was developed using feedback from three clinical PGx-trained pharmacists. 15 Participants independently reviewed the application and assessed usability using the system usability scale (SUS). Results & conclusion: Eighteen different frames were developed. Each video module was 2-3 min for the education. The application included textual information and 3D structures of PGx concepts. The mean SUS score for 15 participants (11 pharmacy students and four pharmacists) was 83, with a standard deviation of 6.6. Results suggest that PGxKnow has the potential to bridge the gap in PGx education, further widespread utilization of PGx and boost its impact on precision medicine.

The feasibility and acceptability of mobile application-based assessment of suicidality using self-report components of a novel tool, the Suicide Ideation and Behavior Assessment Tool (SIBAT).

The aim of this study was to assess the validity of a mobile application-based self-report questionnaire in the assessment of suicidality. We developed a program for the administration of self-report components of the Suicide Ideation and Behavior Assessment Tool (SIBAT). We invited university students and trainees enrolled in a study of addictions to complete this component of the SIBAT using the program on their mobile devices or personal computer. 196 participants completed all required modules of the SIBAT, with 97 using their mobile device and 99 using their personal computer. Rates of completed questionnaires between the two groups were compared, as were the responses to the items and the total scores. There was a significant difference between proportions of scale completion in both groups, with a greater number of participants who used a personal computer to complete the scale not responding to all questions compared to participants who used a mobile device to complete the scale. Data collected via mobile device showed good concurrent validity with data collected via personal computer. A trend toward greater disclosure of suicidality was observed in the mobile device group however, replication of these findings using larger sample sizes is needed.

α-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death.

Abnormalities of α-synuclein (α-syn) and NMDA receptors (NMDARs) are implicated in the pathogenesis of Parkinson's disease. However, how these proteins interact with each other has not been elucidated. Here, the effect of α-syn on NMDARs was investigated by examining the alterations of surface NMDAR NR1 subunits in MES23.5 dopaminergic cells transfected with the human α-syn gene as well as in cells treated with extracellularly added human α-syn. As demonstrated previously that α-syn can enter cells in a non-endocytic manner without being degraded by the cellular proteolytic systems, the extracellularly added α-syn entered the cytoplasm of MES23.5 cells in a concentration-dependent manner. Both the α-syn-transfected cells and α-syn-treated cells exhibited increased intracellular α-syn levels and reduced surface NR1 without altering the total NR1. The α-syn-induced surface NR1 reduction was accompanied by suppression of NMDA-elicited intracellular Ca(2+) elevation and reductions of NMDA-induced caspase 3 activation and cell death, which was abolished by hypotonic shock and K(+) depletion, a procedure that blocks clathrin-mediated endocytosis, and by suppression of RAB5B expression with anti-RAB5B oligonucleotides. The data obtained provide evidence for the first time that α-syn may promote clathrin-mediated NMDAR endocytosis.

Scoping review: the empowerment of Alzheimer's Disease caregivers with mHealth applications.

Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients' caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver.

Internal consistency and concurrent validity of self-report components of a new instrument for the assessment of suicidality, the Suicide Ideation and Behavior Assessment Tool (SIBAT).

This study aimed to assess the internal consistency of self-report components of the Suicide Ideation and Behavior Assessment Tool (SIBAT) and validate it with relevant elements of the Mini International Neuropsychiatric Interview (MINI). The SIBAT is a newly developed instrument for the evaluation of suicidality. In this study, we invited university students and trainees participating in a study of addictions to complete the self-report component of the SIBAT as an add-on study. We evaluated the internal consistency of the self-report component of the SIBAT and validated it against the suicidality component of the MINI. Data were analysed using both complete case analysis and multiple imputation. SIBAT data were collected for 394 participants, 314 of whom had also completed the MINI. The internal consistency of modules 2, 3, and 5 of the SIBAT was high. Each item from module 5 had a statistically significant association with the corresponding item from the MINI. The sum of scores from modules 2 and 3 had a moderate correlation with the assessment of suicide risk determined by the MINI, and a strong correlation with the total score of SIBAT module 5. The completion median time of modules 2, 3 and 5 was 14.3 min.

Artificial Intelligence-Powered Smartphone App to Facilitate Medication Adherence: Protocol for a Human Factors Design Study.

BACKGROUND: Medication Guides consisting of crucial interactions and side effects are extensive and complex. Due to the exhaustive information, patients do not retain the necessary medication information, which can result in hospitalizations and medication nonadherence. A gap exists in understanding patients' cognition of managing complex medication information. However, advancements in technology and artificial intelligence (AI) allow us to understand patient cognitive processes to design an app to better provide important medication information to patients. OBJECTIVE: Our objective is to improve the design of an innovative AI- and human factor-based interface that supports patients' medication information comprehension that could potentially improve medication adherence. METHODS: This study has three aims. Aim 1 has three phases: (1) an observational study to understand patient perception of fear and biases regarding medication information, (2) an eye-tracking study to understand the attention locus for medication information, and (3) a psychological refractory period (PRP) paradigm study to understand functionalities. Observational data will be collected, such as audio and video recordings, gaze mapping, and time from PRP. A total of 50 patients, aged 18-65 years, who started at least one new medication, for which we developed visualization information, and who have a cognitive status of 34 during cognitive screening using the TICS-M test and health literacy level will be included in this aim of the study. In Aim 2, we will iteratively design and evaluate an AI-powered medication information visualization interface as a smartphone app with the knowledge gained from each component of Aim 1. The interface will be assessed through two usability surveys. A total of 300 patients, aged 18-65 years, with diabetes, cardiovascular diseases, or mental health disorders, will be recruited for the surveys. Data from the surveys will be analyzed through exploratory factor analysis. In Aim 3, in order to test the prototype, there will be a two-arm study design. This aim will include 900 patients, aged 18-65 years, with internet access, without any cognitive impairment, and with at least two medications. Patients will be sequentially randomized. Three surveys will be used to assess the primary outcome of medication information comprehension and the secondary outcome of medication adherence at 12 weeks. RESULTS: Preliminary data collection will be conducted in 2021, and results are expected to be published in 2022. CONCLUSIONS: This study will lead the future of AI-based, innovative, digital interface design and aid in improving medication comprehension, which may improve medication adherence. The results from this study will also open up future research opportunities in understanding how patients manage complex medication information and will inform the format and design for innovative, AI-powered digital interfaces for Medication Guides. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21659.

MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system.

Oxidative stress is a major cause of skin injury induced by damaging stimuli such as UV radiation. Currently, owing to their immunomodulatory properties, mesenchymal stem cell-derived exosomes (MSC-Exo), as a nanotherapeutic agent, have attracted considerable attention. Here, we investigated the therapeutic effects of MSC-Exo on oxidative injury in H2O2-stimulated epidermal keratinocytes and UV-irradiated wild type and nuclear factor-erythroid 2-related factor-2 (Nrf2) knocked down cell and animal models. Our findings showed that MSC-Exo treatment reduced reactive oxygen species generation, DNA damage, aberrant calcium signaling, and mitochondrial changes in H2O2-stimulated keratinocytes or UV-irradiated mice skin. Exosome therapy also improved antioxidant capacities shown by increased ferric ion reducing antioxidant power and glutathione peroxidase or superoxide dismutase activities in oxidative stress-induced cell and skin injury. In addition, it alleviated cellular and histological responses to inflammation and oxidation in cell or animal models. Furthermore, the NRF2 signaling pathway was involved in the antioxidation activity of MSC-Exo, while Nrf2 knockdown attenuated the antioxidant capacities of MSC-Exo in vitro and in vivo, suggesting that these effects are partially mediated by the NRF2 signaling pathway. These results indicate that MSC-Exo can repair oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Thus, MSC-Exo may be used as a potential dermatological nanotherapeutic agent for treating oxidative stress-induced skin diseases or disorders.

The efficacy of transcranial alternating current stimulation for treating post-stroke depression: Study Protocol Clinical Trial (SPIRIT Compliant).

BACKGROUND: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation. METHODS: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models. DISCUSSION: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism. TRIAL REGISTRATION NUMBER: NCT03903068, pre-results.

High mobility group box-1 (HMGB1) antagonist BoxA suppresses status epilepticus-induced neuroinflammatory responses associated with Toll-like receptor 2/4 down-regulation in rats.

It has been generally accepted that inflammatory responses induced by status epilepticus (SE) in the brain are associated with microglial activation. One important regulator of microglial activation is high mobility group box-1 (HMGB1) protein. HMGB1 exerts its influence on microglia via various pathways including Toll-like receptor (TLR) subtypes 2 and 4. To explore the HMGB1 role in the SE-induced microglial activation and the involvement of TLRs we conducted in vivo and ex vivo experiments using the HMGB1 antagonist BoxA. Blood-brain barrier (BBB) permeability, brain water content, hippocampal neuroinflammation and neuronal apoptosis were measured 24 h after the pilocarpine induction of status epilepticus (SE) in Sprague-Dawley rats treated with BoxA. In ex vivo experiments, post-SE microglia cells were isolated from the hippocampal CA1 area and subjected to lipopolysaccharide (LPS) stimulation followed by inflammatory cytokine IL-1ß and IL-6 by qPCR and HMGB1, TLR2, TLR3 by Western blotting. A significant down-regulation of IL-1ß, IL-6 and TNF-α but not HMGB1 was found in BoxA-treated compared to untreated animals. These changes were associated with decreased BBB permeability, reduced hippocampal neuronal apoptosis and reduction in hippocampal microglial activation. We conclude that BoxA-induced suppression of HMGB1-mediated neuroinflammatory responses is associated with TLR-2 and 4 down-regulation and should be explored as a potential therapeutic target.

Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice.

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.

Rab-mediated endocytosis: linking neurodegeneration, neuroprotection, and synaptic plasticity?

Rab proteins are small GTPases involved in endocytosis and recycling of cell surface molecules. Recently they have been implicated in the etiopathogenesis of several neurodegenerative disorders including Alzheimer's and Lewy body disease. In experiments on organotypic hippocampal cultures, upregulation of Rab protein family member Rab5b after group I metabotropic glutamate receptor (mGluR) stimulation was associated with reduced neuronal vulnerability to excitotoxic injury. This mGluR-mediated neuroprotection was abolished by antisense-induced deficiency of Rab5b. Electrophysiological measurements of excitatory synaptic transmission in the Schaffer collateral-CA1 pathway revealed that mGluR activation that induces neuroprotection also induced long-term depression (LTD) of synaptic transmission. Similar to the neuroprotection, Rab5b deficiency abolished dihydroxyphenylglycine-induced LTD. Together, these findings support the idea that Rab proteins, and the Rab5b protein in particular, may provide a link between neurodegenerative disease, neuroprotection, and synaptic plasticity, as well as possibly being a useful target for pharmacological interventions.

Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis.

Group I metabotropic glutamate receptor (mGluR) agonist DHPG reduced nerve cell death caused by their exposure to NMDA ("neuroprotective effect") and attenuated NMDA receptor-mediated currents [Blaabjerg, M., Baskys, A., Zimmer, J., Vawter, M. P., 2003b. Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors. Brain Research, Molecular Brain Research 117, 196-205.]. In the present study, we used organotypic hippocampal culture preparation to examine specific phospholipase C (PLC) inhibitor U73122 effects on DHPG-induced neuroprotection, changes in excitatory synaptic transmission associated with the neuroprotective DHPG treatment and a role of group I mGluR ligands in neurogenesis. Results show that short (10 min) DHPG treatment did not result in neuroprotection but significantly depressed field synaptic potentials (fEPSP) in the Schaffer collateral-CA1 pathway. The fEPSP depression was not affected by the PLC inhibitor U73122. In contrast, prolonged (2-h) treatment of cultures with DHPG induced a significant protective effect that was blocked by a PLC inhibitor U73122 but not by its inactive analog U73343. Voltage-clamp measurements of spontaneous miniature excitatory post-synaptic currents (EPSCs) recorded in CA1 neurons from cultures treated with DHPG (10 microM, 2 h) showed a significant reduction of the EPSC amplitude in DHPG-treated but not control (untreated) cultures. This reduction was completely abolished by U73122, suggesting a PLC involvement. Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64. DHPG (100 microM, 72 h) slightly but not significantly increased the number of TOAD-64 positive cells. The mGluR1 antagonists LY367385 (10 microM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 microM, 72 h) had no effect. These data suggest that (1) prolonged activation of group I mGluRs reduces nerve cell susceptibility to excitotoxic injury in a PLC-dependent manner; (2) this reduction is associated with a PLC-dependent depression of excitatory synaptic transmission; and (3) mGluR1 activation may facilitate neurogenesis.

Activation of neuroprotective pathways by metabotropic group I glutamate receptors: a potential target for drug discovery?

Stroke neuroprotection trials suggest that pharmacological manipulations of a single neuroprotective mechanism are generally ineffective and that new approaches, possibly involving simultaneous manipulations of multiple mechanisms, need to be sought. To identify optimal components for such a multipronged approach, we studied NMDA receptor activation-induced cell death in organotypic hippocampal culture preparations as a model of excitotoxicity. Metabotropic group I glutamate receptor (mGluR) activation by their selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), resulted in concentration-dependent reduction of nerve cell susceptibility to NMDA-mediated injury (neuroprotective effect). The neuroprotection was mediated primarily by mGluR1, required phospholipase C activation, was inhibited by cholesterol-containing methyl-beta-cyclodextrin treatment, and occluded by antipsychotic quetiapine. It was associated with suppression of NMDA currents and prolongation of GABA(A) receptor-mediated currents in DHPG-treated cultures. cDNA microarray analysis of 1128 brain-relevant genes revealed that mGluR-mediated neuroprotection was associated with simultaneous activation of endocytosis, and inactivation of inflammation, cell adhesion, cell death, and transcription-related genes. Antisense inhibition of Rab5b, a gene coding for a small GTPase associated with endocytosis, significantly reduced the mGluR-mediated neuroprotection. These findings expand our understanding of the role that mGluRs play in regulation of nerve cell susceptibility to injury and should facilitate the design of novel therapeutic strategies for stroke and other neurodegenerative diseases.

Understanding regulation of nerve cell death by mGluRs as a method for development of successful neuroprotective strategies.

A common cause of nerve cell death often leading to vascular dementia is ischemic stroke. Attempts to develop clinically effective stroke treatment and prevention strategies based on pharmacological manipulations of a single mechanism have not led to clinical success. Analysis of clinical neuroprotection trials suggests that combination treatments may be more effective. To identify optimal components for such treatment, N-methyl-d-aspartate receptor (NMDAR) activation-induced cell death in organotypic hippocampal preparations was studied as a model of neurodegeneration that occurs in association with stroke or vascular dementia. Pharmacological manipulation of metabotropic glutamate receptors mGluR1 and 5 resulted in significant reduction of nerve cell susceptibility to NMDA-induced injury, suggesting that these receptors may function as physiological regulators of neuronal vulnerability. cDNA microarray analysis of over 1000 brain-related genes performed after the neuroprotective activation of group I metabotropic glutamate receptors (mGluRs) revealed a complex pattern of activation and inactivation of seemingly unrelated genes responsible for regulation of neuronal excitability, inflammation, cell death pathways, cell adhesion and transcriptional activation. Combined pharmacological targeting of these processes may provide basis for clinical trials of effective neuroprotective compounds.