ABSTRACT
We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl-]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl-]i levels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson's disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl-]i levels and GABAergic inhibition.
Subject(s)
Cholinergic Neurons/metabolism , Corpus Striatum/metabolism , Inhibitory Postsynaptic Potentials/drug effects , Interneurons/metabolism , Parkinson Disease, Secondary/metabolism , gamma-Aminobutyric Acid/metabolism , Acetylcholine/metabolism , Acetylcholine/pharmacology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Bumetanide/pharmacology , Chlorides/metabolism , Cholinergic Agents/metabolism , Cholinergic Agents/pharmacology , Cholinergic Neurons/drug effects , Cholinergic Neurons/pathology , Corpus Striatum/drug effects , Corpus Striatum/pathology , Dopamine/deficiency , Gene Expression Regulation , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Humans , Interneurons/drug effects , Interneurons/pathology , Ion Transport , LIM-Homeodomain Proteins/genetics , LIM-Homeodomain Proteins/metabolism , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neuronal Plasticity/drug effects , Parkinson Disease, Secondary/genetics , Parkinson Disease, Secondary/pathology , Patch-Clamp Techniques , Sodium Potassium Chloride Symporter Inhibitors/pharmacology , Solute Carrier Family 12, Member 2/genetics , Solute Carrier Family 12, Member 2/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Vesicular Inhibitory Amino Acid Transport Proteins/genetics , Vesicular Inhibitory Amino Acid Transport Proteins/metabolism , gamma-Aminobutyric Acid/pharmacologyABSTRACT
AIMS: To investigate patterns of practice in palliative radiotherapy in Africa. MATERIALS AND METHODS: Fifteen centres in Africa provided detailed information about radiotherapy in both metastatic and locally advanced disease via a questionnaire. Information included general information (institution status, equipment, staff, patient number), radiotherapy and other treatment characteristics in bone metastasis, brain metastasis, metastatic spinal cord compression, lung and liver metastasis, as well as locally advanced tumours. RESULTS: The number of patients annually seen/treated ranged from 285 to 5000. Breast, cervix, head and neck, gastrointestinal and prostate cancer were the top five cancers overall. Eight (53%) institutions were without linear accelerators, four (27%) had a single one, whereas one institution each had two, three and four linear accelerators. The number of cobalt machines ranged from 0 to 2 (median 1). Most centres still prefer to use fractionated radiotherapy regimens over single-fraction regimens in bone metastasis, although most centres are now using single-fraction radiotherapy in retreatments. Radiotherapy in brain metastasis and metastatic spinal cord compression mostly conform to worldwide standards. Lung and liver metastases are rarely irradiated, largely as a consequence of the lack of modern radiotherapy technology. Locally advanced disease in various tumour sites was mostly palliated, in agreement with current evidence-based practices. CONCLUSIONS: African countries still lack adequate staffing and equipment to adequately address their clinical burden, being palliative in most cases. Emphasis should also be made on more rationally using existing capacities by using more of the single-fraction radiotherapy regimens, especially in bone metastasis.
