Homeostatic systems, biocybernetics, and autonomic neuroscience.

In this review we describe a series of major concepts introduced during the past 150years that have contributed to our current understanding about how physiological processes required for well-being and survival are regulated. One can theorize that hierarchical networks involving input-output relationships continuously orchestrate and learn adaptive patterns of observable behaviors, cognition, memory, mood, and autonomic systems. Taken together, these networks function as "good regulators" determining levels of internal variables and act as if there were homeostatic comparators ("homeostats").

Linking Stress, Catecholamine Autotoxicity, and Allostatic Load with Neurodegenerative Diseases: A Focused Review in Memory of Richard Kvetnansky.

In this Focused Review, we provide an update about evolving concepts that may link chronic stress and catecholamine autotoxicity with neurodegenerative diseases such as Parkinson's disease. Richard Kvetnansky's contributions to the field of stress and catecholamine systems inspired some of the ideas presented here. We propose that coordination of catecholaminergic systems mediates adjustments maintaining health and that senescence-related disintegration of these systems leads to disorders of regulation and to neurodegenerative diseases such as Parkinson's disease.

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy.

Background: Severe putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA.

Autoimmunity-associated autonomic failure with sympathetic denervation.

We report a case of autoimmunity-associated autonomic failure in a young adult woman who developed arthritis followed 3 years later by pandysautonomia. There was early recovery of parasympathetic functions but persistent neurogenic orthostatic hypotension from post-ganglionic sympathetic denervation. Clinical laboratory testing indicated variable amounts of sympathetic neuronal re-sprouting in the heart, kidneys, eyes, and body as a whole upon follow-up evaluation after 1.

Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies.

Introduction: There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder.

3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells.

The catecholaldehyde hypothesis predicts that monoamine oxidase (MAO) inhibition should slow the progression of Parkinson's disease, by decreasing production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). Inhibiting MAO, however, diverts the fate of cytoplasmic dopamine toward potentially harmful spontaneous oxidation products, indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels. 3,4-Dihydroxyphenylethanol (hydroxytyrosol) is an abundant anti-oxidant phenol in constituents of the Mediterranean diet.

Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells.

According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors.

Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration.

Several neurodegenerative diseases involve loss of catecholamine neurons--Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"--inherent cytotoxicity caused by catecholamine metabolites.

Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy.

Background: Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern.

Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease.

Repeated systemic administration of the mitochondrial complex I inhibitor rotenone produces a rodent model of Parkinson's disease (PD). Mechanisms of relatively selective rotenone-induced damage to nigrostriatal dopaminergic neurons remain incompletely understood. According to the 'catecholaldehyde hypothesis,' buildup of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to PD pathogenesis.

Plasma biomarkers of decreased vesicular storage distinguish Parkinson disease with orthostatic hypotension from the parkinsonian form of multiple system atrophy.

Background: Parkinson disease with orthostatic hypotension (PD + OH) and the parkinsonian form of multiple system atrophy (MSA-P) can be difficult to distinguish clinically. Recent studies indicate that PD entails a vesicular storage defect in catecholaminergic neurons. Although cardiac sympathetic neuroimaging by (18)F-dopamine positron emission tomography can identify decreased vesicular storage, this testing is not generally available.

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders.

Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced.

A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson's disease.

In Parkinson's disease (PD), profound putamen dopamine (DA) depletion reflects denervation and a shift from vesicular sequestration to oxidative deamination of cytoplasmic DA in residual terminals. PD also involves cardiac sympathetic denervation. Whether PD entails myocardial norepinephrine (NE) depletion and a sequestration-deamination shift have been unknown.

Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease.

Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL),which is toxic. According to the 'catecholaldehyde hypothesis', DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson’s disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase(ALDH) to the increased DOPAL levels found in PD.

Vesicular uptake blockade generates the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease.

Parkinson's disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intraneuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, as α-synuclein oligomers may be pathogenetic in Parkinson's disease, oligomerizes α-synuclein.

Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases.

Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies - cytoplasmic inclusions containing α-synuclein protein aggregates - in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons.

Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS.

Background: L-threo-3,4-dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti-parkinsonian drugs might interact with L-DOPS. We tested whether L-aromatic amino-acid decarboxylase inhibition by carbidopa (CAR) attenuates L-DOPS conversion to NE and blocks the pressor effect of L-DOPS, whereas catechol-O-methyltransferase inhibition by entacapone (ENT) interferes with L-DOPS metabolism and augments the pressor effect.

Hypertension increases cerebral 6-18F-fluorodopa-derived radioactivity.

Unlabelled: 6-(18)F-fluorodopa PET depicts the striatal dopaminergic lesion characterizing Parkinson disease (PD); however, striatal uptake of 6-(18)F-fluorodopa-derived radioactivity can be normal. Supine hypertension (SH) might increase 6-(18)F-fluorodopa uptake.

Methods: We measured putamen, caudate, and occipital cortex 6-(18)F-fluorodopa-derived radioactivity and supine blood pressure in patients with PD + SH (systolic pressure >/= 180 mm Hg, n = 8), patients with PD without SH (PD - SH, n = 19), patients with pure autonomic failure (n = 8), and controls (n = 16).

Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis.

Objective: Exposure to stressors alters activities of the adrenomedullary hormonal system (AHS), hypothalamic-pituitary-adrenocortical (HPA) axis, and sympathetic nervous system (SNS). Here we report results of a meta-analysis of the literature, examining inter-relationships among AHS, HPA, and SNS responses to stressors, as measured by plasma epinephrine (EPI), corticotrophin (ACTH), and norepinephrine (NE) levels.

Methods: The medical scientific literature was culled by PubMed searches, to retrieve publications describing original data about plasma EPI, ACTH, and NE levels measured before and during or after exposure to stressors.

Evolution of concepts of stress.

This essay describes the evolution of stress as a medical scientific idea. Claude Bernard, Walter B. Cannon and Hans Selye provided key founding concepts for the current view.

Clinical catecholamine neurochemistry: a legacy of Julius Axelrod.

1. Discoveries, insights, and concepts that Julius Axelrod introduced about the disposition and metabolism of catecholamines provided the scientific basis and spurred the development of clinical catecholamine neurochemistry. 2.

Catecholamine metabolism: a contemporary view with implications for physiology and medicine.

This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm.

Leaky catecholamine stores: undue waste or a stress response coping mechanism?

Turnover of catecholamines, representing the constant loss and replenishment of neurotransmitter by synthesis, is usually considered to be driven exclusively by catecholamine release. This is incorrect. An important contribution of intraneuronal metabolism of norepinephrine to turnover, and dependence of this on leakage of norepinephrine from vesicular stores, was originally proposed by Kopin in 1964.

Cardiac uptake-1 inhibition by high circulating norepinephrine levels in patients with pheochromocytoma.

Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 micromol/L.