Although intrinsic tumours of the brain seldom metastasize to distant sites, their diffuse, infiltrative-invasive growth within the brain generally precludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that include the use of anti-invasive and anti-proliferative agents. The effect of four anti-invasive agents, swainsonine (a locoweed alkaloid), captopril (an anti-hypertensive drug), tangeretin and nobiletin (both citrus flavonoids), were investigated on various parameters of brain tumour invasion such as matrix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A standard cytotoxicity assay was used to optimize working concentrations of the drugs on seven human brain tumour-derived cell lines of various histological type and grade of malignancy. A qualitative assessment by gelatin zymography revealed that the effect of these agents varied between the seven cell lines such that the low grade pilocytic astrocytoma was unaffected by three of the agents. In contrast, downregulation of the two gelatinases, MMP-2 and MMP-9 was seen in the grade 3 astrocytoma irrespective of which agent was used. Generally, swainsonine was the least effective whereas the citrus flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most efficient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astrocytoma and a glioblastoma multiforme). Yet again, the effects of the four agents varied between the four cell lines. Nobiletin was, nevertheless, the most effective agent used in these assays. In conclusion, the differential effects seen on the various parameters studied by these putative anti-invasive agents may be the result of interference with MMPs and other mechanisms underlying the invasive phenotype. From these pilot studies, it is possible that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a larger study.

This brief review will first consider HIV associated neurocognitive disorder followed by the current understanding of its neuropathogenesis. Against this background the role of the kynurenine pathway will be detailed. Evidence both direct and indirect will be discussed for involvement of the kynurenine pathway at each step in the neuropathogenesis of HIV associated neurocognitive disorder.

Schizophrenia is associated with a number of pathological changes, including alterations in levels of specific proteins. Calprotectin is a novel 36 kDa calcium-binding protein of the S100 family and appears to be a nonspecific marker of inflammation. Calprotectin has not previously been investigated in brain tissue. Samples of post-mortem brain tissue from Brodmann area 9 were obtained from prefrontal cortex from subjects with schizophrenia, bipolar affective disorder, major depression, and from controls. Calprotectin levels were determined by ELISA. To determine cellular localization, immunocytochemical and fluorescent double-labelling analyses were performed. Exogenous calprotectin was added to retinoic acid-differentiated human SH-SY5Y neuroblastoma cell cultures in order to investigate mechanisms of action of calprotectin. Calprotectin was detectable in all samples, and mean levels were noted to be highest in schizophrenic brains (P < 0.05) and lowest in controls. Levels were intermediate in bipolar affective disorder and major depression. Exogenous calprotectin appeared to induce dendritic extension in SH-SY5Y cell culture in a dose-dependent manner. Calprotectin was found to be localized to microglia. These findings suggest that increased levels of calprotecitn in the brain may reflect inflammatory processes, which play a role in the pathogenesis of major psychiatric disorders. Furthermore, calprotectin may influence dendritic plasticity.