Neuroscience and heart-brain medicine: The year in review

July 1, 2010|Cleveland Clinic Journal of Medicine

ABSTRACT

Important recent publications in the area of neuroscience and heart-brain medicine center largely around three topics: (1) mechanisms of cardiac sympathetic denervation in Parkinson disease, (2) cytoplasmic monoamine metabolites as autotoxins, and (3) the validity of power spectral analysis of heart rate variability to indicate cardiac sympathetic tone. Findings by Orimo et al support a centripetal, retrograde pathogenetic process involving alpha-synuclein deposition and degeneration of cardiac noradrenergic neurons in Parkinson disease. Several studies suggest that processes increasing cytoplasmic monoamines lead to neuronal loss from auto-oxidation or enzymatic oxidation. Lack of correlation between commonly used indices from power spectral analysis of heart rate variability and cardiac norepinephrine spillover casts doubt on the validity of power spectral analysis to indicate cardiac sympathetic tone.

CYTOPLASMIC MONOAMINE METABOLITES AS AUTOTOXINS

Current concepts about mechanisms of PD emphasize pathologic alpha-synuclein accumulation, oxidative injury, impaired proteasomal or mitochondrial functions, neuroinflammation, or abnormal kinase signaling. These concepts do not explain relatively selective nigrostriatal dopaminergic and cardiac noradrenergic denervation in PD.

Figure 3. According to the monoamine aldehyde hypothesis, interference with the vesicular recycling of cytoplasmic monoamines (dopamine [DA], norepinephrine [NE], and serotonin [5-HT]) augments formation of toxic aldehydes. For instance, DA that leaks from vesicles (V) into the cytoplasm (C) or that is taken up via the cell membrane DA transporter (DAT) and escapes vesicular reuptake via the vesicular monoamine transporter (VMAT) is subject to oxidative deamination catalyzed by monoamine oxidase (MAO) to form the catecholaldehyde DOPAL, which is toxic. DOPAL is detoxified by ALDH to form DOPAC, the major metabolic route, or by AR to form DOPET, the minor metabolic route. Analogously, NE is converted to DOPEGAL, and 5-HT is converted to 5-HT-aldehyde (5-HTAld).

A potential explanation is that cytoplasmic catecholamine metabolites are autotoxins (Figure 3). The mechanisms of autotoxicity include spontaneous auto-oxidation, to form quinones and chromes leading to increased production of reactive oxygen species, and enzymatic oxidation.

Catecholamines in the neuronal cytoplasm undergo enzymatic oxidative deamination to form catecholaldehydes (dihydroxyphenylacetaldehyde [DOPAL] from dopamine), which are cytotoxic, as predicted by Blaschko more than a half century ago.¹⁰ DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH). In the substantia nigra, aldehyde dehydrogenase 1A1 (ALDH1A1) is the main isoform of ALDH, and postmortem studies have noted decreased nigral ALDH1A1 gene expression^11,12 and protein content¹³ in PD patients.

All neurons express alpha-synuclein. Current concepts about mechanisms also do not explain the relatively selective aggregation of alpha-synuclein in catecholaminergic neurons. Alpha-synuclein appears to play a role in the cycling of catecholamines across vesicular and cell membranes.¹⁴

Figure 4. Cell survival and cytoplasmic dopamine are inversely related, according to a murine model by Mosharov et al.16 Graph shows the dependence of cell survival under l-dopa–induced stress on the cytoplasmic dopamine (DAcyt) dose in mouse neurons. The DAcyt dose was estimated as: [DAcyt]×TExposure = [DAcyt]×Ln([L-dopa]/K0.5)/k,where [DAcyt] is the concentration of cytosolic DA in cells treated with a saturating level (> 50 μM) of l-dopa for 1 hour, where [l-dopa] is the initial drug concentration, and where K0.5 = 9.7 μM and k = 0.15 hr−1 are the kinetic constants. TExposure approximates the time during which extracellular l-dopa remained higher than K0.5. The data points are (from left to right): **filled circles**—ventral midbrain cultures treated with 25, 100, 250, 500, and 1,000 μM l-dopa alone; **open circles**—ventral midbrain neurons treated with 250 μM l-dopa in the presence of benserazide, methamphetamine, reserpine, pargyline, and pargyline reserpine; **diamonds**—ventral tegmental area and substantia nigra neurons; **triangles**—striatal and cortical neurons treated with 250 μM l-dopa. Dotted lines and shaded boxes represent mean ± SEM in untreated cells. The solid line is the linear fit of all data points, excluding striatal and cortical neurons and the two data points indicated by the asterisk. Treatments to the right of this line are neuroprotective, as the same level of cell death is achieved with higher DAcyt doses; treatments to the left of this line are more susceptible to DAcyt stress.

In the past year, a few important studies have been published related to autotoxicity of cytoplasmic catecholamine metabolites and to pathogenic interactions with alpha-synuclein. In 2006, Mosharov et al reported that alpha-synuclein overexpression increases cytoplasmic dopamine concentrations in rat pheochromocytoma PC-12 cells.¹⁵ Recently, the same group, using intracellular patch electrochemistry, directly measured cytoplasmic dopamine in cultured midbrain neurons and found that increases in dopamine and its metabolites are neurotoxic, whereas manipulations that reduce cytoplasmic dopamine are neuroprotective (Figure 4).¹⁶ Levodopa (l-dopa) increased cytoplasmic dopamine more in substantia nigra neurons than in ventral tegmental neurons, suggesting that this difference might help explain the greater susceptibility of nigral neurons to the pathogenetic process. The greater buildup of cytoplasmic dopamine seemed to depend on dihydropyridine-sensitive calcium (Ca²⁺) channels. Finally, dopaminergic neurons lacking alpha-synuclein were resistant to l-dopa–induced cell death. These findings led the authors to propose a “multiple-hit” model (Figure 5) in which interactions between intracellular ionized calcium, cytoplasmic dopamine, and alpha-synuclein underlie susceptibility of nigral neurons in PD.¹⁶

Figure 5. The “multiple-hit” model of Parkinson disease pathogenesis,16 which holds that neurotoxicity is a result of multiple factors, including the presence of alpha-synuclein (α-syn), elevation of cytoplasmic calcium (Ca2+), and buildup of cytoplasmic dopamine (DAcyt) and its metabolites. Nonexclusive toxic steps may result from (1) mechanisms that require direct interaction between DA or its metabolites with α-syn, such as DA-modified stabilization of α-syn protofibrils or inhibition of chaperone-mediated autophagy, or (2) cumulative damage from multiple independent sources. Reducing the levels of any of the three players provides neuroprotection. (AADC = aromatic l-amino acid decarboxylase; DOPAL = dihydroxyphenylacetaldehyde; TH = tyrosine hydroxylase)

Burke et al added a potentially important clue, demonstrating that DOPAL potently oligomerizes and aggregates alpha-synuclein.¹⁷ This finding introduces the possibility of multiple pathogenetic positive feedback loops.

Under resting conditions, most catecholamine turnover results from leakage from vesicular stores into the cytoplasm and subsequent oxidative deamination by monoamine oxidase. Ordinarily, however, catecholamines in the cytoplasm are efficiently recycled back into the vesicles via the type 2 vesicular monoamine transporter (VMAT-2). Accordingly, interference with VMAT functions would be expected to tend to build up cytoplasmic catecholamines, with potentially cytotoxic consequences. In 2007, Caudle et al reported that mice with severely decreased VMAT-2 have aging-associated decreases in striatal dopamine that begin in the terminal fields, alpha-synuclein deposition in substantia nigra neurons, and l-dopa–responsive behavioral deficits.¹⁸ More recently the same group noted nonmotor signs associated with PD in VMAT-2–deficient mice, such as anosmia, gastrointestinal hypomotility, sleep disturbances, anxiety, and depression.¹⁹ Since VMAT-2 serves to recycle not only dopamine but also norepinephrine and serotonin, this single abnormality could help explain loss of all three types of monoaminergic neurons in PD.

Finally, Pena-Silva et al recently tested whether serotonin induces oxidative stress in human heart valves.²⁰ They showed that in heart valves from explanted human hearts not used for transplantation, incubation of homogenates of cardiac valves and blood vessels with serotonin increased generation of the superoxide free radical. Inhibitors of monoamine oxidase prevented this effect. Dopamine also increased superoxide levels in heart valves, and this effect was also attenuated by monoamine oxidase inhibition. These findings fit with the concept that the aldehydes produced by the action of monoamine oxidase on cytoplasmic monoamines generate toxic free radicals.

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