Fumio Moriwaka

Neurotoxicity of methylglyoxal and 3‐deoxyglucosone on cultured cortical neurons: Synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases

In this study, we investigate the neurotoxicity of glycation, particularly early‐stage glycation, and its mechanisms, which are possibly synergized with oxidative stress. Methylglyoxal (MG) and 3‐deoxyglucosone (3DG), intermediate products of glycation, are known to further accelerate glycation and advanced glycation endproducts (AGEs) formation. Both compounds showed neurotoxicity on cultured cortical neurons and these effects were associated with reactive oxygen species production followed by neuronal apoptosis. Pretreatment with N‐acetylcysteine induced neuroprotection against MG and 3DG. Cotreatment, but not pretreatment, with aminoguanidine protected neurons against the neurotoxicities of both compounds. The present study provides the first evidence that MG and 3DG are neurotoxic to cortical neurons in culture. Interference with the process by which glycation and AGEs formation occur may provide new therapeutic opportunities to reduce the pathophysiological changes associated with neurodegeneration, if, as indicated here, the participation of glycoxidation in the pathogenesis of neurodegenerative diseases is essential. J. Neurosci. Res. 57:280–289, 1999.

Effect of 1,25-dihydroxyvitamin D3 on cultured mesencephalic dopaminergic neurons to the combined toxicity caused by L-buthionine sulfoximine and 1-methyl-4-phenylpyridine

A decrease in intracellular glutathione content may be related to the primary event in Parkinsons disease, so increasing the glutathione level may have a therapeutic benefit. The biologically active form of vitamin D, 1,25‐dihydroxyvitamin D3 [1,25‐(OH)2D3] has been recently reported to enhance the intracellular glutathione concentration in the central nervous system. Exposing rat cultured mesencephalic neurons for 24 hr to a mixture of L‐buthionine sulfoximine (BSO) and 1‐methyl‐4‐phenylpyridium ions (MPP+) resulted in a relatively selective damage to dopaminergic neurons. This damage has been accompanied by a reduction of intracellular glutathione levels. Low doses, i.e., 1–100 nM, of 1,25‐(OH)2D3 protect cultured dopaminergic neurons against this toxicity, although higher concentrations of this active form of vitamin D have been found to enhance the toxic effect. Generation of reactive oxygen species (ROS) by this toxicity has been attenuated in cultures being pretreated with low concentrations of 1,25‐(OH)2D3. Because the hormone increases the intracellular glutathione content in cultures, determining how this hormone suppresses ROS generation may involve the enhancement of the antioxidative system. These data suggest that low doses of 1,25‐(OH)2D3 are able to protect mesencephalic dopaminergic neurons against BSO/MPP+‐induced toxicity that causes a depletion in glutathione content. J. Neurosci. Res. 62:374–382, 2000.

Selective vulnerability of spinal motor neurons to reactive dicarbonyl compounds, intermediate products of glycation, in vitro : implication of inefficient glutathione system in spinal motor neurons

We investigated the effects of two reactive dicarbonyl compounds, methylglyoxal (MG) and 3-deoxyglucosone (3-DG), on cultured spinal cord neurons. Incubation of cortical and spinal neurons with MG and 3-DG for 24 h induced neuronal death in a dose-dependent manner. Spinal motor neurons were more vulnerable than spinal non-motor neurons and cortical neurons. Treatments with glutathione (GSH)-augmenting agents showed protective effects against MG and 3-DG neurotoxicity. Motor neurons were better protected than non-motor neurons. Cotreatment, but not pretreatment, of aminoguanidine (AG), a known inhibitor of advanced glycation end-products (AGEs) from crosslinking, showed a protective effect on spinal neurons with no difference in protective rates between motor and non-motor spinal neurons. Treatments with GSH depleting agents enhanced the neurotoxicity of MG and 3-DG on spinal neurons. Motor neurons were more vulnerable than non-motor neurons with GSH-depleting treatments prior to MG and 3-DG exposures. These data demonstrate that spinal motor neurons are more vulnerable to dicarbonyl compounds, and this selectivity might be related to the relatively inefficient GSH system in spinal motor neurons.

Anticardiolipin antibodies in Japanese patients with multiple sclerosis

We evaluated circulating anticardiolipin antibodies (aCL) in 38 Japanese patients who fulfilled the criteria of clinically definite multiple sclerosis (MS), using a newly developed EIA system with aCL‐cofactor. Two of 38 patients (5.3%) had a aCL‐cofactor‐dependent positive serology, and differences compared with findings in controls were statistically significant. The 2 aCL‐positive patients had similar clinical features with acute transverse myelopathy (ATM), optic neuropathy (OPN), normal cranial MRI and negative oligoclonal IgG bands (OCBs) in the cerebrospinal fluid (CSF). Among the 38 patients, 3 had ATM, OPN, normal cranial MRI and negative OCBs, hence, in a significant number of the patients (2/3; 67%) with these distinctive features, serology for aCL was positive. Therefore, they may have another condition associated with aCL, masquerading as MS. Serological testing for aCL with aCL‐cofactor is recommended for the patients with clinical diagnosis of MS, especially for those showing OPN and ATM during the clinical course, and in Asian peoples where the incidence of ATM and OPN is relatively high among the patients with diagnosis of MS.

Protective effects of the TNF-ceramide pathway against glutamate neurotoxicity on cultured mesencephalic neurons

Pretreatments with TNF-alpha and lower concentrations of C2-ceramide protected cultured mesencephalic neurons from excitotoxicity in a dose-dependent manner. These protective effects are reduced by cotreatment with N,N-dimethylsphingosine (DMS), an inhibitor of sphingosine kinase. Since the pretreatment with sphingosine-1-phosphate (SPP) showed a neuroprotective effect, our data suggest that protective effects of TNF and C2-ceramide could be attributable to their further metabolism to SPP.

Acute transverse myelopathy in multiple sclerosis

Sixty-two consecutive patients with clinically definite multiple sclerosis (MS) were classified into 2 subgroups: group A, consisting of 16 patients who had shown acute transverse myelopathy (ATM) during the course of illness; and group B, 46 patients without ATM. The clinical features of these 2 groups were analysed prospectively for certain periods, and some significant differences were found. There was (1) later onset, (2) less frequent occurrence of brain stem, cerebellar and cerebral symptoms, (3) more frequent and severe involvement of the optic nerve, (4) a smaller proportion of patients with abnormal findings on brain MRI in group A compared with group B. The clinical features of group B were quite similar to those of previous Western series, while group A seemed to constitute a distinct clinical subgroup in patients with MS.

Facial palsy in multiple sclerosis.

Abstract Facial palsy occurred in 21 (19.6%) of 107 Japanese patients with multiple sclerosis (MS) during a mean follow-up period of 4.3 years. We observed residual signs of facial palsy in five other patients in whom acute onset was confirmed from medical records. Facial palsy began on average 7.6 years after the onset of MS but in five patients (4.7%) was the first symptom of MS, preceding the next MS symptom by 0.5–3 years. Facial palsy was usually associated with other brainstem signs, while two patients showed only facial palsy 1 and 3 years after the onset of MS. Twenty-one (84.0%) of the 25 patients who underwent brain magnetic resonance imaging (MRI) showed brainstem lesions in the pontine tegmentum ipsilateral to the facial palsy. However, the two patients without other symptoms or signs had no apparent causal lesion on MRI, which suggests difficulty in differentiating idiopathic Bell’s palsy from MS- associated facial palsy by MRI, although it has an excellent capacity to detect causal lesions of facial palsy associated with MS.

Progressive multifocal leucoencephalopathy with magnetic resonance imaging verification and therapeutic trials with interferon

SummaryProgressive multifocal leucoencephalopathy was diagnosed by magnetic resonance imaging (MRI) and brain biopsy in a 44-year-old woman, for whom therapeutic trials with various antiviral agents were made. Despite early diagnosis and treatment, her neurological deterioration and extension of MRI-detectable lesions were not halted for a period of about 8 months. After the introduction of intrathecal β-interferon therapy, her neurological status and MRI findings became stable and showed minimal improvement. Early diagnosis of this fatal disorder is important and intrathecal interferon therapy should be considered.

Myelopathy due to osteochondroma: MR and CT studies

A 9-year-old boy with multiple osteochondromas developed progressive transverse myelopathy. Magnetic resonance imaging and CT demonstrated an exostosis at C7-T1 with cord compression.

Androgen receptor abnormality in X‐linked spinal and bulbar muscular atrophy

X-linked spinal and bulbar muscular atrophy (SBMA) is usually associated with feminization and hypogonadism. We were unable to find androgen receptor (AR) in the scrota) skin of three patients with SBMA, and propose that AR abnormality is the cause of the disease.