Asenapine effects in animal models of psychosis and cognitive function

Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, α-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties. The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone. Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01–0.3 mg/kg s.c.), Apo-PPI (0.001–0.3 mg/kg s.c.), DNMTP (0.01–0.1 mg/kg s.c.), and 5-CSR (0.003–0.3 mg/kg s.c.). Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03–0.3 mg/kg; and risperidone, 0.01–0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05). Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone

Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice

Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer’s disease (AD). Acetylcholine contributes to localised arterial dilatation and increased cerebral blood flow (CBF) during neurovascular coupling via activation of endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested to contribute to impaired clearance of β-amyloid (Aβ) along intramural periarterial drainage (IPAD) pathways of the brain, leading to the development of cerebral amyloid angiopathy (CAA). However, the possible relationship between loss of cholinergic innervation, impaired vasoreactivity and reduced clearance of Aβ from the brain has not been previously investigated. In the present study, intracerebroventricular administration of mu-saporin resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. Arterial spin labelling MRI revealed a loss of CBF response to stimulation of eNOS by the Rho-kinase inhibitor fasudil hydrochloride in the cortex of denervated mice. By contrast, the hippocampus remained responsive to drug treatment, in association with altered eNOS expression. Fasudil hydrochloride significantly increased IPAD in the hippocampus of both control and saporin-treated mice, while increased clearance from the cortex was only observed in control animals. Administration of mu-saporin in the TetOAPPSweInd mouse model of AD was associated with a significant and selective increase in Aβ40-positive CAA. These findings support the importance of the interrelationship between cholinergic innervation and vascular function in the aetiology and/or progression of CAA and suggest that combined eNOS/cholinergic therapies may improve the efficiency of Aβ removal from the brain and reduce its deposition as CAA

Revelando o vírus, ocultando pessoas: exames de monitoramento (CD4 e CVP) e relação médico-paciente no contexto da AIDS Disclosing the virus, hiding the patients: follow-up tests (CD4 and VL) and the physician-patient relationship in the AIDS setting

O objetivo deste artigo é discutir os significados associados aos exames de contagem de linfócitos CD4 e quantificação da carga viral plasmática do HIV (CVP) para pacientes vivendo com AIDS e médicos da atenção, buscando analisar os reflexos de sua crescente utilização na relação terapêutica. Foi realizado um estudo qualitativo em dois centros de referência em HIV/AIDS com observação participante e entrevistas semi-estruturadas com 27 pacientes vivendo com AIDS e quatro médicos. A observação das consultas médicas mostrou que elas são rápidas, objetivas e centradas no resultado dos exames CD4 e CVP, o que reforça uma visão hegemônica do saber médico e uma perspectiva biomédica que instrumentaliza a sua prática. Para médicos e pacientes, os exames passam a refletir a "verdade" sobre a doença do paciente em detrimento da anamnese e do exame clínico, fato que se reflete na relação terapêutica e na desatenção por parte dos médicos à subjetividade dos pacientes. Mais do que nunca há necessidade da retomada da prática da boa clínica e do reconhecimento do papel do sujeito na prática da medicina como arte de curar.<br>The aim of this study is to discuss the meanings associated with the CD4 lymphocyte count and HIV plasma viral load (VL) for patients living with AIDS and the attending physicians, seeking to analyze the impacts of the increasing use of these tests in the treatment setting. A qualitative study was performed in two HIV/AIDS referral centers with participant observation and semi-structured interviews with 27 patients living with AIDS and four physicians. Observation of the medical consultations showed that they are quick, objective, and centered on the CD4 and VL test results, thus reinforcing a hegemonic view of medical knowledge and a biomedical perspective that instrumentalizes their practice. For physicians and patients, the tests tend to reflect the "truth" on the patient's disease, to the detriment of the patient history and clinical examination, impacting the therapeutic relationship and leading to the physician's lack of attention to the patients' subjectivity. More than ever, there is a need to reclaim good clinical practice and acknowledge the subject's role in medical practice as a healing art