Activation of catechol‐O‐methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons

Abstract

Elevation of the total homocysteine (tHcy) concentration in plasma has been implicated in neurodegeneration in patients with stroke, dementia, Alzheimer disease, and Parkinson disease. Because the mechanisms controlling brain tHcy are unknown, the present study investigated its synthesis and transport in primary rat brain cell cultures. We found that the catechol-O-methyltransferase (COMT) substrate 3,4-dihydroxybenzoic acid (DHB) increased export of tHcy in astrocytes, but not in neurons. The export mechanism was selective for tHcy over cyst(e)ine, total glutathione (tGSH) or cysteinylglycine (Cys-Gly). tHcy export from astrocytes was also induced by the COMT substrates levodopa (L-DOPA), dopamine and quercetin, and it was blocked by the COMT inhibitors tropolone and entacapone. This export was associated with increased synthesis of tHcy because both intracellular and extracellular tHcy concentrations rose during COMT activation. Incubation in cyst(e)ine-deficient medium inhibited the tHcy export response to COMT activation. Exogenous tHcy (100 muM) was accumulated into neurons, but not into astrocytes. We conclude that activation of COMT causes sustained synthesis of Hcy in astrocytes and transport of this amino acid to neurons.

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

“…In addition to its presence in the blood, HCY also arises in many brain areas after catechol-O-methyltransferase (COMT) methylates synaptically released dopamine (DA) and norepinephrine (NE) (Bigl et al 1974;Broch Jr. and Fonnum 1972;Huang et al 2005;Tunbridge et al 2008). HCY is present in normal human cerebrospinal fluid (CSF), and schizophrenia patients show increased HCY in the CSF (Regland et al 2004), but studies that have addressed the synaptic actions of extracellular HCY have produced complex results.…”

“…This occurs after DA breakdown by COMT in astrocytes (Huang et al 2005). HCY is also cleared from the extracellular space by an as yet uncharacterized neuronal transporter (Huang et al 2005). If HCY is released from astrocytes into the synaptic cleft, it could reach glutamate or DA-like concentrations (ϳ1 mM).…”

The blood–brain barrier-permeable catechol-O-methyltransferase inhibitor dinitrocatechol suppresses experimental autoimmune encephalomyelitis

“…The modified NA is normetaneprhine, which can be further metabolized by MAO to normetanephrine aldehyde. COMT is expressed in the CNS, predominantly in astrocytes (Muller et al, 1993;Huang et al, 2005) as well as in microglial cells (Helkamaa et al, 2007) and in some neurons (Myohanen et al, 2010). COMT inhibitors have been in use for many years as a co-treatment for Parkinson's disease (Muller, 2009;Nord et al, 2010), to reduce the breakdown of the dopamine precursor levodopa and increase central bioavailability (Muller, 2009).…”

“…COMT can methylate certain coumarins, a large family of molecules found in a variety of plants (Venugopala et al, 2013), and which have multiple functions including anti-inflammatory and anti-oxidant functions; COMT inhibitors could increase the levels of anti-oxidant coumarins and structurally related molecules. In astrocytes, COMT increases homocysteine synthesis, which can be exported and taken up by neurons as a source of cysteine (Huang et al, 2005).…”

Acute Effects of Vitamin C Exposure On Colonic Crypts: Direct Modulation of pH Regulation

“…In previous studies, this absorption of Vitamin C was associated with Glucose transport [11, 12]. If this relationship to Na-dependent Glucose transport can be exploited, it may be possible to enhance the uptake of Vitamin C and thus further provide an antitumorigenic effect [13].…”