Lipids of nervous tissue: composition and metabolism.

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

https://www.europeanurology.com/article/S0302-2838(05)00822-5/pdf/proposed-mechanism-for-the-efficacy-of-injected-botulinum-toxin-in-the-treatment-of-human-detrusor-overactivity

Proposed Mechanism for the Efficacy of Injected Botulinum Toxin in the Treatment of Human Detrusor Overactivity

Background: Treatment of human bladder overactivity with intradetrusor Botulinum-A neurotoxin (BoNT/A) injections temporarily blocks the presynaptic release of acetylcholine from the parasympathetic innervation and produces a paralysis of the detrusor smooth muscle. The efficacy of the treatment exceeds that expected from simple detrusor muscle paralysis, however, and its effect of reducing urgency is greatly welcomed by patients. Objectives: To examine whether BoNT/A has a complex effect on sensory mechanisms by inhibiting vesicular release of multiple excitatory neurotransmitters by urothelial and suburothelial nerves and reducing axonal expression of SNARE-complex dependant proteins. Methods: A literature review. Conclusions: We propose that a primary peripheral effect of BoNT/A is the inhibition of release of acetylcholine, ATP, substance P, and reduction in the axonal expression of the capsaicin and purinergic receptors. This may be followed by central desensitization through a decrease in central uptake of substance P and neurotrophic factors. The summation of these effects is a profound and long-lasting inhibition of those afferent and efferent mechanisms that are thought to be the pathophysiological basis for DO.

https://europeanurology.com/article/s0302-2838(05)00822-5/pdf/proposed-mechanism-for-the-efficacy-of-injected-botulinum-toxin-in-the-treatment-of-human-detrusor-overactivity

Review - Neuro-urology - Voiding Dysfunction Proposed Mechanism for the Efficacy of Injected Botulinum Toxin in the Treatment of Human Detrusor Overactivity

The case is compelling for the involvement of nerve growth factor (NGF) in the pathogenesis of lower urinary tract disease, especially in conditions with altered neural function. Remodeling of the micturition pathways occurs following experimental bladder-outlet obstruction, denervation, spinal cord injury, cystitis, and diabetes mellitus. Clinically, NGF levels are elevated in the bladders of men with benign prostatic hyperplasia, women with interstitial cystitis and in patients with idiopathic overactive bladder. Blockade of NGF, using either an endogenous antibody or an antibody against the NGF receptor, prevents neural plasticity and bladder overactivity in experimental models of these conditions. The ability of NGF to trigger bladder overactivity might rely on altering the properties of sodium or potassium channels (or their expression) in bladder afferent fibers. Therapies based on altered NGF levels, or changes in channel properties in afferent nerves, represent an intriguing avenue of investigation for the management of detrusor overactivity or diabetic cystopathy.

https://www.nature.com/articles/ncpuro0408.pdf?proof=t

Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders.

Enzymic synthesis of ether types of choline and ethanolamine phosphoglycerides by microsomal fractions from rat brain and liver.

CDPcholine and CDpethanolamine prevent the release of free fatty acids during brain ischemia

Reversibility of ethanolamine and choline phosphotransferases (EC 2.7.8.1 and EC 2.7.8.2) in rat brain microsomes with labelled alkylacylglycerols

The 1-alkyl-2-acyl, 1-alk-1'-enyl-2-acyl, and 1,2-diacyl-snglycerol moieties of choline and ethanolamine glycerophospholipids were converted to the dinitrobenzoyl derivatives. These compounds were separated by high performance liquid chromatography and quantitated by their absorbance at 235 nm. Peak areas were proportional to the amount injected. Separations were optimal for the derivatives from 5 to 30 nmol of the glycerophospholipids. The compositions of ethanolamine glycerophospholipids from rat brain and of choline and ethanolamine glycerophospholipids from human platelets agreed well with previous results obtained with much longer procedures.

Quantitative Analysis of Alkylacyl, Alkenylacyl, and Diacyl Types of Diglycerides Obtained from Glycerophospholipids

Glycerophospholipids have important roles in biological processes. In addition to forming the hydrophobic backbone of cell membranes, glycerophospholipids also participate actively in signal transduction. A number of receptors respond to agonist-binding by activation of a phospholipase C that hydrolyzes PtdIns 4,5-P2 to InsP3 and diacylglycerols (Berridge and Irvine, 1984; Berridge et al., 1985; Berridge, 1986; Nishizuka, 1984a, b; Hirasawa and Nishizuka, 1985; Abdel-Latif et al., 1985; Akhtar and Abdel-Latif, 1986). The InsP3 may increase cytosolic Ca2+ concentrations, thus activating a protein kinase and other reactions. The diacylglycerol stimulates protein kinase C.

G. Goracci

Papers

Enzymic synthesis of ether types of choline and ethanolamine phosphoglycerides by microsomal fractions from rat brain and liver.

CDPcholine and CDpethanolamine prevent the release of free fatty acids during brain ischemia

Reversibility of ethanolamine and choline phosphotransferases (EC 2.7.8.1 and EC 2.7.8.2) in rat brain microsomes with labelled alkylacylglycerols

Quantitative Analysis of Alkylacyl, Alkenylacyl, and Diacyl Types of Diglycerides Obtained from Glycerophospholipids

Modern Techniques for the Fractionation and Purification of Phospholipids from Biological Materials