An increasing body of evidence indicates a role for oligomers of the amyloid-? peptide (A?) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of A? have been noted ranging from the larger Amyloid ?-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of A?. More recently a dodecameric form of A? with a 56 kDa molecular weight, denoted A?*56, was shown to cause memory impairment in AD model mice.
The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic.
INTRODUCTION: Bipolar disorder (BD) is a common psychiatric disorder which can be devastating to affected patients, if not adequately treated. Although effective drugs are presently available for treating BD, many patients do not respond adequately. There are also problems with the current management of patients with this disorder: drug-resistant BD, rapid-cycling BD and cognitive decline in BD patients despite drug therapy. In this context, new and more effective drugs will be valuable in the clinical management of BD patients.
Two new GABA derivatives, 1 and 2, were synthesized and tested for their capacity to display CNS activity, which was assessed by determining the effects on the duration of pentobarbital-induced hypnosis in rats. Compound 1, peripherally injected, significantly prolonged the hypnosis time, a typical GABA-mimetic effect, while both intracerebroventricular and intravenous administration of compound 2 surprisingly shortened the hypnotic effect in an atropine-sensitive way. The study was extended also to compounds 1a, 1b and 2a, putative oxidative/hydrolytic metabolites of 1 and 2.
Gamma hydroxybutyric acid (GHB), an endogenous constituent of the mammalian brain, acts as i) a neurotransmitter or neuromodulator, ii) a medicine used for the treatment of narcolepsy and alcoholism, and iii) a drug illicitly used for its psychotropic effects. GHB is thought to act as a specific GHB receptor agonist as well as a weak gamma-aminobutyric acid type B (GABA(B)) receptor agonist. Here, I review the in vivo and in vitro pharmacological properties of GHB and its interaction with GHB and GABA(B) receptors.
Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-IRBC) in postcapillary brain endothelium is a hallmark of cerebral malaria (CM) pathogenesis. There is a correlation between adherent Pf-IRBC and increased expression of intercellular cell adhesion molecule 1 (ICAM-1), which is also a receptor for Pf-IRBC on human brain microvascular endothelial cells (HBMEC). The underlying mechanism for the increased ICAM-1 expression has not been clearly defined. Therefore, we investigated the mechanisms of ICAM-1 expression on isolated HBMEC after exposure to Pf-IRBC.
BACKGROUND: Central to the pathologic progression of human cerebral malaria (CM) is sequestration of Plasmodium falciparum-infected red blood cells (Pf-IRBCs) to the blood-brain barrier (BBB) endothelium. The molecular interactions between Pf-IRBCs and the BBB endothelium and their implications for barrier function are unclear. METHODS: The effects of Pf-IRBCs on the integrity of the BBB were assessed by electrical cell substrate sensing and by transendothelial electrical resistance measurements in an in vitro human BBB model.
BACKGROUND: Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. So far, however, the tissue distribution and metabolic profile of DHA data are not available from animal and humans. METHODS: Pharmacokinetics, tissue distribution, mass balance, and elimination of [14C] DHA have been studieded in rats following a single intravenous administration. Protein binding was performed with rat and human plasma.
The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFN? and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model.