Levels ofpros-methylimidazoleacetic acid: Correlation with severity of Parkinson's disease in CSF of patients and with the depletion of striatal dopamine and its metabolites in MPTP-treated mice

Abstract

The cerebrospinal fluid (CSF) levels of pros-methylimidazoleacetic acid (p-MIAA) in thirteen medication-free patients with mild to moderate Parkinson's disease were highly correlated (Spearman's rho = 0.749, p less than 0.005) with the severity of signs of the disease as scored on the Columbia University Rating Scale. Levels of p-MIAA in males (n = 8) and females (n = 5) were each significantly correlated with scores of severity (rho = 0.78, p less than 0.05 and rho = 1.0, p less than 0.05, respectively). In C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), levels of p-MIAA were significantly correlated with the depleted levels of dopamine (r = 0.85, p less than 0.01), homovanillic acid (r = 0.79, p less than 0.02), 3,4-dihydroxyphenylacetic acid (r = 0.84, p less than 0.01) and norepinephrine (r = 0.91, p less than 0.002) in striatum, but not in cortex of the same mice. No such correlations were observed in either striatum or cortex of saline-treated control mice. Mean levels of p-MIAA in CSF did not differ significantly between patients and age-matched controls; and mean levels of p-MIAA in striatum did not differ between MPTP-treated mice and controls. The simplest hypothesis to account for these strong correlations in the absence of differences in mean levels of p-MIAA is that accumulation of p-MIAA [or process(es) that govern its accumulation] influences a failing nigrostriatal system. It is also possible (in analogy with findings in other diseases and with other drugs) that measurements of the putative metabolite(s) of p-MIAA may distinguish the patients and the MPTP-treated mice from their respective controls. Elucidation of the processes that regulate formation and disposition of p-MIAA in brain and information on the neural effects of p-MIAA, its precursors and its putative metabolites may yield insight into factors that regulate the progression of Parkinson's disease, and may shed additional light on the cause(s) of this disease.

The human histaminergic system in neuropsychiatric disorders

“…Interestingly, the unaltered expression of HDC was combined with a strong accumulation of Lewy bodies (LBs) and Lewy neurites (LNs), which are characteristic neuropathological PD markers that occur early in the disease process in the TMN [34,35] (Table 1). Thus, these data suggest that there is no increase in endogenous histamine production during the course of PD, which is in line with findings of intact numbers of histaminergic neurons [36], the unchanged enzyme activity of HDC [37], and the unaltered CSF tMeHA levels in PD [38]. Some studies reported an increased density of histaminergic fibers in the SN [39,12] and increased local histamine levels in the SN of patients with PD [33].…”

Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease

“…CSF levels of pros-methylimidazol acetic acid, an isomer of the histamine metabolite tele-methylimidazol acetic acid, have been found to be decreased in PD (Prell et al, 1991), and were highly positively correlated with the severity of the disease (Prell and Green, 1991). …”

Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons

“…In addition, some HA metabolites and derivatives have been correlated with the degree of severity in PD patients. Levels of pros-methylimidazolacetic acid in cerebrospinal fluid showed a high positive correlation with the severity of PD in a group of not medicated, mildly to moderately affected patients [112, 113]. Further indications supporting the involvement of HA in the etiopathology of PD come from the observation that an increase in HA concentration was associated with the appearance or worsening of parkinsonian symptoms.…”