Induction of GADD45α protects M17 neuroblastoma cells against MPP*.

Growth arrest and DNA-damage-inducible protein 45α (GADD45α) is an important member of the family of growth arrest and DNA damage-inducible (GADD) proteins. The expression patterns and possible roles of GADD45α in Parkinson's disease (PD) are so far less understood. In this study, we found that 1-methyl-4-phenylpyridinium (MPP+) treatment up-regulates the expression of GADD45α in both a time-dependent manner and a dose-dependent manner in human dopamine neuroblastoma M17 cells. The up-regulation of GADD45α was abolished by pretreatment with the c-Jun N-terminal kinases (JNK) inhibitor SP600125 but not the p38 specific inhibitor SB203580. Further study revealed that c-Jun silencing abolished the effects of MPP+ on the expression of GADD45α. Important, ChIP studies verified the ability of c-Jun to bind to the GADD45 promoter. In addition, we found that inhibition of GADD45α by small RNA interference exacerbates the impaired cell viability, LDH release, and apoptosis induced by MPP+. Correspondingly, silence of GADD45 exacerbated Caspase-3 activation induced by MPP+. These data suggested a neuroprotective effect of GADD45α against MPP+ neurotoxicity.

[Association of cytochrome P4502D6 gene polymorphism with the susceptibility of heroin spongiform leucoencephalopathy].

OBJECTIVE: To elucidate the relation between cytochrome P4502D6 (CYP2D6) gene polymorphism and the susceptibility of heroin spongiform leucoencephalopathy (HSLE). METHODS: With polymerase chain reaction-restriction fragment length polymorphism technique, the cytochrome P4502D6 gene polymorphisms were analyzed in HSLE cases and control subjects. RESULTS: The frequencies of CYP2D6 (CYP2D6/C188, CYP2D6/L2938, CYP2D6/G4268) gene mutations were higher in HSLE patients than in the controls. CONCLUSION: The CYP2D6 gene mutation is associated with a high risk of HSLE.

[Clinical and neuroimaging features of heroin spongiform leukoencephalopathy].

OBJECTIVE: To summarize the clinical and radiographic characteristics of heroin spongiform leukoencephalopathy (HSLE). METHODS: A clinical analysis of 42 cases of HSLE was conducted. RESULTS: Clinically, the patients with HSLE all had a positive history of inhalation of heated heroin vapor with acute or subacute onset in most cases, presenting initially cerebellar signs. Pyramidal tract lesion was frequently involved, but the sensory system usually remained normal. The consciousness disturbances may occur in the serious cases. Brain CT and magnetic resonance imaging (MRI) revealed extensive symmetric white matter lesions in the cerebrum and cerebellum, and in serious cases, the midbrain and pons could be damaged. Spongiform vacuoles degeneration of white matter characterized the predominant pathological changes. CONCLUSION: Spongiform leukoencephalopathy should be considered in a patient who shows acute cerebellar signs and reports a history of inhaling heated heroin vapor, and a definite diagnosis of HSLE can be made in such a case upon the identification of typical CT or MRI findings.

[Roles of bcl-2/bax expression and oligodendrocyte apoptosis in the pathogenesis of heroin-induced spongiform leucoencephalopathy].

OBJECTIVE: To investigate the role of oligodendrocyte apoptosis under the regulation of the bcl-2/bax protein expression in brain white matter in the pathogenesis of heroin-induced spongiform leucoencephalopathy (HSLE). METHODS: Samples of frontal lobe, cerebellum, and corpus callosum were obtained from the brains during autopsy of 4 HSLE cases and 5 normal controls and underwent light microscopy and electron microscopy. Immunocytochemistry was used to detect the expression of myelin basic protein (MBP), caspase-3, bcl-2 protein, and bax protein. RESULTS: Widespread demyelination was seen in the white matter of the frontal lobe, cerebellum and corpus callosum of the HSLE cases, most severely in the cerebellum. The levels of caspase-3 and bax expression of the HSLE group were significantly higher than those of the control group (both P <0.05) , however, the bcl-2 level of the HSLE group was no significantly different from that of the control group (P > 0.05). CONCLUSION: Widespread demyelination in the white matter is a prevailed pathological change of HSLE. Oligodendrocyte apoptosis under induced by the decrease of bcl-2/bax ratio may contribute to the pathogenesis.

[Pathological analysis of heroin spongiform leukoencephalopathy].

OBJECTIVE: To investigate the pathological characteristics of heroin spongiform leukoencephalopathy (HSLE). METHODS: Cerebral tissue specimens were obtained from 15 patients with HSLE and the histological observations under optical and electron microscopes were carried out by HE, Bielschowsky's, and chromotrope 2R-brilliant green staining. RESULTS: HSLE was characterized primarily by spongiform vacuolar degeneration of the cerebral white matter. Neurons in the gray matter, Purkinje and granular cells in the cerebella remain intact in all the cases. Numerous vacuoles, which merged to form larger cavities, appeared in the damaged white matter, and the axons survived in the deep white matter. The myelin sheath in the cerebellar white matter sustained more severe damages than those in the cerebral white matter. No vacuoles or lymphocyte infiltration occurred in the small peripheral vessels. CONCLUSION: HSLE is pathologically characterized by vacuolar degeneration due to primary damage of the myelin, and the spongiform vacuolar degeneration is closely associated with the severity of demyelination in the white matter.

[Surgical procedure improvement to produce rat ischemia-reperfusion injury model with intraluminal suture].

OBJECTIVE: To describe a modified surgical approach to produce rat ischemia-reperfusion injury model with intraluminal suture. METHODS: After exposure and ligation of the common carotid artery (CCA), the left external carotid artery and pterygopalatine artery were opened in which a 3-0 nylon suture was introduced intraluminally from the distal end of the ligature of the CCA using a scalp needle. Reperfusion injury was induced by withdrawal of the suture. RESULTS: The length of the suture was about 20.0+/-1.8 mm and the success rate of model establishment was nearly 70%. The rats developed typical symptoms and pathological manifestations after the surgery. CONCLUSION: This modified surgical approach is simple for model establishment and does not require special microsurgical skills to ensure the high success rate.

C242T p22phox gene polymorphism in the population of Han nationality in Guangdong province.

This study aimed to investigate the gene polymorphism of the C242T p22phox in the population of Han nationality in Guangdong Province by randomly selecting 122 unrelated healthy candidates examined by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). It was found that the C and T allele frequencies were 0.934 and 0.066, and CC and CT+TT genotype frequencies were 0.877 and 0.123, respectively, in the population of Han nationality in Guangdong Province, suggesting the presence of C242T p22phox gene polymorphism with significant racial differences.

[Glucocortioid treatment for heroin-induced spongiform leucoencephalopathy: a clinical controlled study].

OBJECTIVE: To evaluate the therapeutic effects of the glucocorticoid on heroin-induced spongiform leucoencephalopathy. METHODS: Twenty cases of heroin-induced spongiform leucoencephalopathy were randomly divided into the control group and the treating group with equal number. In the control group, the treatment was constituted by oral administration of vitamin B and coenzyme Q10 in a course of 1 month. In glucocorticoid treatment group, glucocorticoid (20 mg/d) for 10 d were given in addition to vitamin B and coenzyme Q10, and the dose of the glucocorticoid was gradually decreased afterwards. General observation and statistical analysis of function scores were performed in both groups before and 1, 6, 12 months after the treatment respectively. RESULTS: No significant difference in function scores was observed between the 2 groups, while the results of observation before and after the treatment were significantly different (P<0.05). The most significant difference occurred when comparing the observations made 1 month and 6 months respectively after treatment (P<0.001). CONCLUSION: Glucocorticoid has no obvious therapeutic effect on heroin-induced spongiform leucoencephalopathy, and rapid clinical recovery occurs within the initial 6 months of the treatment.

Single photon emission computerized tomography of spongiform leukoencephalopathy heroin addicts: analysis of 10 cases.

OBJECTIVE: To investigate the changes in cerebral circulation in heroin addicts with pongiform leukoencephalopathy. METHODS: Single photon emission computerized tomography (SPECT) was performed in 10 such patients. RESULTS: Regional cerebral blood flow (rCBF) in the involved white matter of bilateral cerebral and cerebellar hemispheres was obviously reduced. rCBF of temporal lobes, parietal lobes, cerebellar hemispheres and basal ganglion were reduced in varying degrees. CONCLUSION: As demonstrated by the result of SPECT, rCBF in the white matter of bilateral cerebral and cerebellar hemispheres was reduced with partial involvement of the gray matter of heroin addicts with spongiform leukoencephalopathy.

Brain Accumulation of Amyloid-beta in Non-Alzheimer Neurodegeneration.

We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by extensive cerebral amyloid-beta deposition in small and medium-size vessels, capillaries, and perivascular plaques in the cerebral cortex, and in most leptomeningeal vessels. Despite considerable cerebral amyloidosis, the patient remained cognitively intact until death. For comparison with other neuro-degenerative diseases and normal aging, we assessed the densities of amyloid-beta-immunoreactive cortical vessels and plaques in matched frontal and temporal lobe sections from archival uncomplicated cases of Alzheimer's disease (N=10), Pick's disease (PkD; N=4), Parkinson's disease (PD; N=6), Diffuse Lewy body disease (DLBD; N=7), progressive supranuclear palsy (PSP; N=5), multiple systems atrophy (MSA; N=4), ALS (N=7), or normal aging (N=10) by semi-quantitative grading (0 to 3+). Moderate (2+) or abundant (3+) cerebrovascular amyloid-beta immunoreactivity was detected in 8/10 AD, 3/7 DLBD, 3/6 PD, 1 each with PSP or PkD, and 2/10 controls. Moderate or abundant densities of amyloid-beta-immunoreactive diffuse plaques were detected in all cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls. Moderate or abundant amyloid-beta-immunoreactive mature (dense core) plaques were present in all cases of AD or DLBD, and 3 each with PD or PSP. Importantly, amyloid-beta-immunoreactivity was not observed in the 4 MSA or 7 archival ALS cases. This study demonstrates that prominent amyloid-beta accumulation in cerebral vessels and plaques occurs frequently in AD, DLBD, PSP, and PD, but not in ALS or MSA, indicating that the case described is unique. The lack of cognitive impairment in the case presented argues against the idea that extensive amyloid-beta deposition in the brain causes dementia.