Pharmacology of Endogenous Neurotoxins

A Neurotoxins.- 1 Isoquinoline Derivatives.- 1. Introduction.- 2. Tetrahydroisoquinoline (TIQ).- 2.1 Presence of TIQ in nature and in food.- 2.2 Methods for identification and measurement of TIQ.- 2.3 Presence of TIQ in tissues.- 2.4 Endogenous synthesis of TIQ.- 2.5 Parkinsonism caused by TIQ.- 2.6 Metabolism of TIQ in the brain.- 3. 1,2-Dihydroisoquinoline.- 4. 4-Hydroxy-TIQ.- 5. 1-Benzyl-TIQ.- 6. 1-Phenyl-N-methyl-TIQ and 1-phenyl-TIQ.- 7. Salsolinol (SAL).- 7.1 Presence of SAL in tissues, body fluids, food, and nature.- 7.2 Biosynthetic pathway of SAL.- 7.3 Neurotoxicity of SAL.- 7.4 Metabolism of SAL.- 8. Norsalsolinol.- 9. N-Methyl-salsolinol and N-methyl-norsalsolinol.- 10. 1,2,3,4-Tetrahydro-2-methyl-4,6,7-i soquinolinetriol.- 11. Methods for identification and measurement of catecholic TIQs.- 12. The sites of toxicological activity.- 12.1 Inhibition of mitochondrial respiratory enzymes.- 12.2 Hydroxyl radical formation.- 2 TIQ Derivatives in the Human Central Nervous System.- 1. History of the Presence of TIQ derivatives.- 2. Analytical Methods.- 2.1 Cerebrospinal Fluid (CSF).- 2.1.1 Lumbar Puncture.- 2.1.2 High Performance Liquid Chromatography.- 2.2 Urine.- 2.2.1 Urine measurements of Salsolinol.- 2.2.2 Affinity chromatography.- 2.2.3 High Performance Liquid Chromatography.- 3. Frequency and TIQ Levels measured by HPLC-ECD.- 3.1 N-Methyl-norsalsolinol.- 3.2 Salsolinol.- 4. TIQ Derivatives and Dopamine Metabolites.- 5. Stereospecifity and Enantiomeric Separation.- 6. Cerebral Lesions by TIQ Derivatives.- 6.1 TIQ, 1-Methyl-TIQ, 2-Methyl-TIQ.- 6.2 N-Methyl-[R]-salsolinol.- 6.3 N-Methyl-norsalsolinol.- 6.4 N-Methyl-4-hydroxy-norsalsolinol.- 7. Hallucinosis and TIQ Derivatives.- 3 Animal Model of Parkinson’s Disease Prepared by N-Methyl-R-Salsolinol.- 1. MPTP and N-Methylation.- 2. Preparation of a rat model of Parkinson’s disease.- 2.1 Materials.- 2.2 Animal experiments.- 3. Behavior observation.- 3.1 Behavior changes due to perturbation in dopaminergic system.- 4. Biochemical analysis in the brain.- 4.1 Methods.- 4.2 Quantitative analyses of monoamines, their metabolites and isoquinolines.- 4.3 Enantiomeric analysis of salsolinol derivatives.- 4.4 Assay of tyrosine hydroxylase activity.- 4.5 Biochemical changes by infusion of N-methyl-[R]-salsolinol and DMDHIQ+.- 4.6 Changes of monoamines and their metabolites.- 4.7 Accumulation of N-methyl-[R]-salsolinol and DMDHIQ+.- 4.8 Reduction of tyrosine hydroxylase activity.- 5. Histological study.- 5.1 Methods for histological analysis.- 5.2 Cytotoxicity in the striatum.- 5.3 Depletion of dopamine neurons in the substantia nigra.- 6. Discussion.- 4 Putative Endogenous Neurotoxins Derived from the Biogenic Amine Neurotransmitters.- 1. Introduction.- 2. Alzheimer’s disease.- 3. Ischemia-Reperfusion.- 4. Methamphetamine.- 5. In vitro oxidation chemistry of the biogenic amine neurotransmitter.- 5.1 In vitro oxidation chemistry of 5-hydroxytryptamine.- 5.2 In vitro oxidation chemistry of dopamine.- 5.3 In vitro oxidation chemistry of norepinephrine.- 6. In vivo oxidation chemistry of the biogenic amine neurotransmitter.- 6.1 In vivo oxidation of 5-hydroxytryptamine.- 6.2 In vivo oxidation of dopamine and norepinephrine.- 7. Properties of putative aberrant oxidative metabolites of the biogenic amine neurotransmitters.- 7.1 Redox properties of putative aberrant oxidative metabolites of 5-HT and 5-HTPP.- 7.2 Redox properties of putative aberrant oxidative metabolites of DA and NE.- 8. Neurochemical and neurobiological properties of putative aberrant oxidative metabolites of 5-HT, DA and NE.- 9. Serotonin binding proteins.- 10. Discussion.- 11. Summary.- 5 ?-Carboline Derivatives as Neurotoxins.- 1. Biosynthetic and organic synthetic routes to TH?C’s and ?C’s.- 2. Overview of the effects of ?C’s and their metabolic derivatives on the nervous system.- 3. Measurement and analysis of TH?C’s, ?C’s and their derivatives.- 4. Enzymatic formation of N-methylated ?C cations from nonpolar ?C’s.- 5. Uptake and intracellular actions of N-methylated ?C cations.- 6. Neurotoxicity in vitro of N-methylated ?C cations.- 7. Neurotoxicity in vivo of N-methylated ?C cations.- 8. Endogenous presence of TH?C’s, ?C’s and their N-methylated derivatives in animals and humans.- 6 Highly Halogenated Tetrahydro-?-Carbolines as a New Class of Dopaminergic Neurons.- 1. Introduction.- 2. Chloral-derived THBCs as potential mammalian alkaloids with expected neurotoxic properties.- 2.1 Synthetic route for the preparation of TaClo.- 2.2 TaClo as a chiral compound: elucidation of the absolute configuration.- 2.3 Ability of TaClo to cross the blood-brain barrier.- 2.4 De novo formation of TaClo in rats treated with its putative precursors.- 3. Lesion studies.- 3.1 Effects of TaClo in cell culture on cell integrity and dopamine metabolism.- 3.2 Inhibition of the mitochondrial respiration.- 3.3 Behavioral studies on rats after intraperitoneal application of TaClo.- 3.4 Striatal dopamine metabolism in the rat after intranigral injection of TaClo.- 4. Outlook.- 7 pros -Methylimidazoleacetic Acid: A Potential Neurotoxin in Brain?.- 1. Introduction.- 2. Biochemical origin of p-MIAA.- 3. Presence of p-MIAA in nature.- 4. Methods of measurement of p-MIAA.- 5. Localization of p-MIAA in brain.- 6. p-MIAA in CSF of patients with Parkinson’s disease.- 7. p-MIAA and studies with mice given MPTP.- 8. p-MIAA and release of the excitoneurotoxin, glutamate.- 9. p-MIAA measured in CSF of patients with chronic schizophrenia.- 10. p-MIAA in brain and lack of changes with drugs.- 11. Summary and conclusions.- B Metabolism.- 8 Bioactivation of Azaheterocyclic Amines Via S-adenosyl-L-methionine-dependent N-methyltransferases..- 1. Methyltransferase.- 1.1 Nicotinamide N-methyltransferase.- 1.2 Histamine N-methyltransferase.- 1.3 Phenylethylamine N-methyltransferase.- 1.4 Amine N-methyltransferase.- 1.5 Others.- 2. Assay procedures.- 3. Methyl donor, SAM.- 4. Substrate for N-methyltransferase, neurotoxin precursor.- 4.1 MPTP analogues.- 4.2 ?-Carbolines and their tetrahydro forms.- 4.3 TIQ and 6,7-DHTIQ.- 4.4 1-Aromatic substitution of TIQs.- 5. Possible formation of azaheterocyclics via SAM-dependent N-methylation.- 9 Tyrosine Hydroxylase: Biochemical Properties and Short-term Regulation In Vitro and In Vivo.- 1. Basic properties of tyrosine hydroxylase.- 2. Structure and function.- 3. Assays for tyrosine hydroxylase.- 4. Regulation of tyrosine hydroxylase.- 4.1 Feedback inhibition.- 4.2 Enzyme phosphorylation and activation in vitro.- 4.3 Regulation of tyrosine hydroxylase by protein phosphorylation and by dopamine autoreceptor in dopaminergic nerve terminals.- 10 Tyrosine Hydroxylase and Endogenous Neurotoxins.- 1. Tyrosine hydroxylase.- 1.1 Genetic aspects: Transcription and translation.- 1.2 Molecular structure.- 1.3 Investigation of tyrosine hydroxylase expression.- 1.4 An assay of tyrosine hydroxylase enzyme activity.- 2. The effect of neurotoxins on tyrosine hydroxylase.- 2.1 Models of neurotoxicity involving tyrosine hydroxylase.- 2.2 Quinoline and isoquinoline derivatives.- 2.3 ?-Carbolines.- 3. Summary.- 11 Monoamine Oxidase: Interaction with Isoquinoline Derivatives.- 1. Monoamine oxidase.- 1.1 Introduction.- 1.2 Classification.- 1.3 Genetic differences.- 1.4 Occurrence.- 1.5 Reaction mechanism.- 1.6 Ravin cofactor.- 2. Interaction between MAO and isoquinoline derivatives.- 2.1 MPTP-model.- 2.2 MPTP-like substances.- 2.3 Isoquinoline derivatives.- 2.4 Isoquinoline derivatives as MAO inhibitor.- 2.5 Inhibition pattern of N-methyl-norsalsolinol.- 2.6 Chemical structure and inhibitory activity.- 12 Toxicity and Pharmacological Effects of Salsolinol in Different Cultivated Cells.- 1. Blood-brain barrier.- 2. Technical procedures.- 2.1 Materials.- 2.2 Cell culture.- 2.3 Cytotoxicity.- 2.4 Electron microscopy.- 2.5 Effect of salsolinol on the ?-endorphin release of AtT-20 cells.- 2.6 Effect of salsolinol on the POMC gene expression.- 2.7 Receptor binding analysis.- 2. Cytotoxicity of salsolinol.- 3. Binding studies with salsolinol on dopamine receptor subtypes.- 4. Effect of salsolinol on POMC gene expression and ?-endorphin release of AtT-20 cells.