GABA transport and neuroinflammation are coupled in multiple sclerosis: regulation of the GABA transporter-2 by ganaxolone.

Interactions between neurotransmitters and the immune system represent new prospects for understanding neuroinflammation and associated neurological disease. GABA is the chief inhibitory neurotransmitter but its actions on immune pathways in the brain are unclear. In the present study, we investigated GABAergic transport in conjunction with neuroinflammation in models of multiple sclerosis (MS). Protein and mRNA levels of γ-amino butyric acid transporter 2 (GAT-2) were examined in cerebral white matter from MS and control (Non-MS) patients, in cultured human macrophages, microglia and astrocytes, and in spinal cords from mice with and without experimental autoimmune encephalomyelitis (EAE) using western blotting, immunocytochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). GABA levels were measured by HPLC. The GAT-2's expression was increased in MS patients' (n=6) white matter, particularly in macrophage lineage cells, compared to Non-MS patients (n=6) (p<0.05). Interferon-γ (IFN-γ) stimulation of human macrophage lineage cells induced GAT-2 expression and reduced extracellular GABA levels (p<0.05) but soluble GABA treatment suppressed HLA-DRα, GAT-2 and XBP-1/s expression in stimulated macrophage lineage cells (p<0.05). Similarly, the synthetic allopregnanolone analog, ganaxolone (GNX), repressed GAT-2, JAK-1 and STAT-1 expression in activated macrophage lineage cells (p<0.05). In vivo GNX treatment reduced Gat-2, Cd3ε, MhcII, and Xbp-1/s expression in spinal cords following EAE induction (p<0.05), which was correlated with improved neurobehavioral outcomes and reduced neuroinflammation, demyelination and axonal injury. These findings highlight altered GABAergic transport through GAT-2 induction during neuroinflammation. GABA transport and neuroinflammation are closely coupled but regulated by GNX, pointing to GABAergic pathways as therapeutic targets in neuroinflammatory diseases.

Analysis of the economic burden of diagnosis and treatment of tuberculosis patients in rural China.

SETTING: A county in Jiangsu Province, China. OBJECTIVES: To estimate the costs of the diagnosis and treatment of tuberculosis (TB) from the patient's perspective and to identify determinants of the patient's financial burden. DESIGN: In a cross-sectional survey, we interviewed 316 patients diagnosed from January 2010 to May 2011 who had already completed their anti-tuberculosis treatment. The financial burden on TB patients included out-of-pocket costs and productivity losses. RESULTS: The average per capita total out-of-pocket cost was 3024.0 Chinese yuan (CNY), with a median cost of 1086 CNY (interquartile range [IQR] 480-2456). Mean out-of-pocket medical and non-medical costs were respectively 2565.7 CNY and 458.3 CNY. Productivity lost by patients and family members was 2615.2 CNY (median 500, IQR 250-2025). Factors associated with out-of-pocket costs and productivity losses included hospitalisation, adverse drug reactions, cost of drugs to 'protect' the liver, cost of second-line anti-tuberculosis drugs and diagnostic delay. CONCLUSION: Although the government of China has implemented a 'free TB service policy', the economic burden on patients is still heavy. More patient-centred interventions are essential to reduce the financial burden on patients.