Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor.

BACKGROUND: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies. METHODOLOGY: Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups. CONCLUSION: The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.

Unique expression patterns of 5-HT2A and 5-HT2C receptors in the rat brain during postnatal development: Western blot and immunohistochemical analyses.

Serotonin (5-HT) is recognized as a potential regulatory factor in neuronal development. Two subtypes of receptors for it, 5-HT2A and 5-HT2C, are distributed broadly in the rat brain, suggesting their role in a variety of brain functions. Here, we investigated the expression patterns of these 5-HT2 receptors in the rat brain during postnatal development by using Western blot and immunohistochemical analyses. By Western blot analysis, the expression of the 5-HT2A receptor was at a low level at postnatal day 3 (P3) and increased greatly during the first 3 postnatal weeks; whereas the 5-HT2C receptor was already expressed at a high level at P3, and its expression increased only slightly during postnatal development. Immunohistochemical analysis showed the different expression patterns of 5-HT2A and 5-HT2C receptor subtypes during postnatal development: the transient expression of the 5-HT2C receptor was observed in layer IV of the somatosensory, visual, and auditory cortices from P10 to P28, and in the thalamus, mainly in the ventral posterolateral and ventral posteromedial nuclei, from P7 to P21; however, the immunoreactivity of the 5-HT2A receptor was detectable slightly at P3, but thereafter the intensity of immunolabeling increased with postnatal development and at P21 reached the adult level and pattern. These results suggest that 5-HT2 receptors have potential significance in brain development, with a functional difference between 5-HT2A and 5-HT2C receptor subtypes.

Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress.

Previously we found that some cyclopenteone prostaglandin derivatives (PGs), referred to as neurite outgrowth-promoting PGs (NEPPs), have dual biological activities of promoting neurite outgrowth and preventing neuronal death [Satoh et al. (2000) J. Neurochem., 75, 1092-1102; Satoh et al. (2001) J. Neurochem., 77, 50-62; Satoh et al. (2002) In Kikuchi, II. (ed.), Strategenic Medical Science Against Brain Attack. Springer-Verlag, Tokyo, pp. 78-93]. To investigate possible cellular mechanisms of the neuroprotective effects, we performed oligo hybridization-based DNA array analysis with mRNA isolated from HT22, a cell line that originated from a mouse hippocampal neuron. Several transcripts up-regulated by NEPP11 were identified. Because heme oxygenase 1 (HO-1) mRNA was the most prominently induced and was earlier reported to protect neuronal and non-neuronal cells against oxidative stress, we focused on it as a possible candidate responsible for the neuroprotective effects. We found NEPP11 to induce HO-1 protein (32 kDa) in HT22 cells in both the presence and the absence of glutamate, whereas non-neuroprotective prostaglandins (PGs) Delta12-PGJ2 or PGA2 did not. Overexpression of HO-1-green fluorescence protein (GFP) fusion protein significantly protected HT22 cells against oxidative glutamate toxicity, whereas that of GFP alone did not. Furthermore, biliverdin and bilirubin, products of HO-1 enzymatic activity on heme, protected HT22 cells from oxidative glutamate toxicity. These results, together with our previous results, suggest that NEPP11 activates the expression of HO-1 and that HO-1 produces biliverdin and bilirubin, which result in the inhibition of neuronal death induced by oxidative stress. NEPP11 is the first molecular probe reported to have a neuroprotective action through induction of HO-1 in neuronal cells.