clozapine and Stroke

Trapeziometacarpal osteoarthritis is associated with more pain and restrictions than other hand osteoarthritis due to the functional importance of the thumb. While the effectiveness of surgical and pharmacological interventions has been widely examined, there is a lack of specific evidence about conservative non-pharmacological trapeziometacarpal osteoarthritis therapies. The objective of this systematic review was to provide evidence-based knowledge on the effectiveness of physiotherapy and occupational therapy on pain, function and quality of life.. A literature search of Medline, CINAHL, PEDro, OTseeker, EMB Dare Cochrane Database of Systematic Reviews and Cochrane CENTRAL was performed. Randomized and quasi-randomized controlled trials and corresponding systematic reviews, observational studies, pragmatic studies and case-control studies were included. The risk of bias was assessed.. Physical and occupational therapy-related interventions, especially multimodal interventions, seem to be effective to treat pain in patients with trapeziometacarpal osteoarthritis. Pre-fabricated neoprene splints and custom-made thermoplastic splints may reduce pain equally. Single interventions seem not to be effective. Significant evidence for effectiveness on function and quality of life could not be found.. The sole Na. The SUV. Genetic variants of

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Long-term disabilities induced by stroke impose a heavy burden on patients, families, caregivers, and public health systems. Extensive studies have demonstrated the therapeutic value of neuromodulation in enhancing post-stroke recovery. Among them, chemogenetic neuromodulation activated by clozapine-N-oxide (CNO) has been proposed as the potential tool of neuromodulation. However, recent evidence showed that CNO does not cross the blood - brain barrier and may in fact have low binding affinity for chemogenetic tool. Thus, clozapine (CLZ) has been suggested for use in chemogenetic neuromodulation, in place of CNO, because it readily crosses the blood-brain barrier. Previously we reported that low doses of CLZ (0.1 mg/kg) successfully induced neural responses without off-target effects. Here, we show that low-dose clozapine (0.1 mg/kg) can induce prolonged chemogenetic activation while avoiding permeability issues and minimizing off-target effects. In addition, clozapine-induced excitatory chemogenetic neuromodulation (CLZ-ChemoNM) of sensory-parietal cortex with hsyn-hM3Dq-YFP-enhanced motor recovery in a chronic capsular infarct model of stroke in rats, improving post-stroke behavioral scores to 56% of pre-infarct levels. Longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET (FDG-microPET) scans showed that a reduction in diaschisis volume and activation of corticostriatal circuits were both correlated with post-stroke recovery. We also found c-Fos increases in bilateral cortices and BDNF increases in the cortices and striatum after CLZ-ChemoNM, indicating an increase in neural plasticity. These findings suggest the translational feasibility of CLZ-ChemoNM for augmenting recovery in chronic stroke.

Topics: Animals; Clozapine; Infarction; Rats; Stroke

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability in a murine model of photothrombotic stroke and show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.

Topics: Animals; Clozapine; Humans; Interneurons; Mice; Neural Inhibition; Receptor, Muscarinic M3; Recovery of Function; Somatosensory Cortex; Stroke; Vasoactive Intestinal Peptide

Ischemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.. We generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.. Detailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.. Our data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.

Topics: Animals; Cells, Cultured; Clozapine; Cortical Spreading Depression; Electrophysiological Phenomena; Evoked Potentials; Male; Mice; Mice, Transgenic; Motor Cortex; Neuroprotection; Prosencephalon; Psychomotor Performance; Reperfusion Injury; Stroke; Synapses; Treatment Outcome

Elevated brain levels of apolipoprotein D (ApoD) correlate with improved neurological recovery after experimental stroke. Hence, a pharmacological induction of ApoD in the postischemic brain could be beneficial for recovery after stroke. Here we investigated the effect of Clozapine, a compound that increases the expression of ApoD, in two rat models of experimental stroke. Rats were subjected to permanent occlusion of the middle cerebral artery (pMCAO) and treated with Clozapine (i.p. 10 mg/kg body weight) or saline for 8 or 28 days starting on the second day after MCAO. ApoD levels increased by 35% in the peri-infarct area after 10 and 30 days after pMCAO, mainly in neuron-specific nuclear protein (NeuN) positive neurons and glial fibrillary acidic protein (GFAP) positive astrocytes. Clozapine did not affect the neurological deficit assessed by the rotating pole test and a grip strength test at 7 days, 14 days, 21 days, and 28 days after pMCAO. Functional outcome and the infarct size were similar in rats subjected to transient MCAO and injected with Clozapine (i.p. 10 mg/kg body weight) or saline for 26 days starting on the second day after tMCAO. We conclude that Clozapine affects cellular processes involved in peri-infarct tissue reorganization, but does not affect functional recovery after MCAO.

Topics: Animals; Apolipoproteins D; Blotting, Western; Clozapine; Disease Models, Animal; Fluorescent Antibody Technique; Infarction, Middle Cerebral Artery; Male; Microscopy, Confocal; Neuroprotective Agents; Rats; Rats, Wistar; Recovery of Function; Stroke

Topics: Administration, Oral; Aged; Antipsychotic Agents; Aripiprazole; Arrhythmias, Cardiac; Benzodiazepines; Clozapine; Databases, Factual; Dementia; Dibenzothiazepines; Drug Utilization Review; Health Services for the Aged; Humans; Olanzapine; Pharmaceutical Services; Piperazines; Quetiapine Fumarate; Quinolones; Risk Assessment; Risperidone; Stroke; Thiazoles; Treatment Outcome

Concern exists about a possible increased risk of cerebrovascular events (CVEs) among elderly patients receiving risperidone or olanzapine. We estimated the effect of atypical and conventional antipsychotics on the risk of CVEs among elderly nursing home patients with dementia.. We conducted a case-control study on residents of nursing homes in 6 U.S. states by using the Systematic Assessment of Geriatric drug use via Epidemiology database, which includes data from the Minimum Data Set linked to Medicare inpatient claims. Participants were diagnosed with Alzheimer's disease or other forms of dementia on the basis of clinical criteria and medical history (including medical records and neuroradiologic documentation). Cases included patients hospitalized for stroke or transient ischemic attack between June 30, 1998, and December 27, 1999. For each case, we identified up to 5 controls hospitalized for septicemia or urinary tract infection residing in the same facility during the same time period. The sample consisted of 1130 cases and 3658 controls.. After controlling for potential confounders, the odds ratio of being hospitalized for CVEs was 0.87 (95% CI = 0.67 to 1.12) for risperidone users, 1.32 (95% CI = 0.83 to 2.11) for olanzapine users, 1.57 (95% CI = 0.65 to 3.82) for users of other atypical agents, and 1.24 (95% CI = 0.95 to 1.63) for conventional antipsychotic users compared to nonusers of antipsychotics. A history of CVEs appeared to modify the effect of atypical antipsychotics other than risperidone on the risk of new events.. Overall, no increased risk of CVEs seems to be conferred by atypical or conventional antipsychotics. Preexisting cerebrovascular risk factors might interact with some atypical antipsychotics to increase the risk of events. These results should be interpreted in light of the limitations of the study and need to be confirmed.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Cerebrovascular Disorders; Clozapine; Comorbidity; Dementia; Female; Geriatric Assessment; Hospitalization; Humans; Ischemic Attack, Transient; Male; Medical Records Systems, Computerized; Nursing Homes; Odds Ratio; Olanzapine; Risk Factors; Stroke; United States

Stroke-induced hemiballismus (HB) has been reported to improve motor function in people with Parkinson's disease (PD). We report on a patient who developed HB from a parietal infarct. The HB was improved by very low-dose clozapine but the HB did not improve the parkinsonism. This suggests that HB itself, whether from a lesion in the subthalamic nucleus or elsewhere, is not what improves motor function in PD; instead, the physiological function of the damaged structure is the determining factor.

Topics: Aged; Antipsychotic Agents; Clozapine; Dyskinesias; Humans; Infarction, Anterior Cerebral Artery; Magnetic Resonance Imaging; Male; Parkinson Disease; Stroke

Topics: Age Factors; Aged; Antipsychotic Agents; Clozapine; Cohort Studies; Health Behavior; Humans; Hypertension; Middle Aged; Myocardial Infarction; Myocarditis; Risk Assessment; Stroke; United States