Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia / La atorvastatina protege las neuronas gabérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Materials and methods: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. Results: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Conclusion: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Introducción. La isquemia cerebral es la tercera causa de muerte y la primera de discapacidad permanente en el mundo. La atorvastatina es un fármaco neuroprotector prometedor para el tratamiento de la apoplejía; sin embargo, su acción sobre las poblaciones neuronales del sistema nigroestriatal después de la isquemia aún se desconoce. Objetivo. Evaluar el efecto de la atorvastatina sobre poblaciones gabérgicas y dopaminérgicas en regiones exofocales en un modelo de oclusión transitoria de la arteria cerebral media. Materiales y métodos. Se utilizaron 28 ratas Wistar macho de ocho semanas de edad. Los ejemplares con isquemia simulada y los ejemplares sometidos a isquemia fueron tratados con atorvastatina (10 mg/kg) y carboximetilcelulosa (placebo) administrados por medio de sonda a las 6, 24, 48 y 72 horas después de la reperfusión. Se analizó la inmunorreacción de la descarboxilasa del ácido glutámico y de la tirosina hidroxilasa en el globo pálido, el putamen caudado y la sustancia negra. Resultados. Los datos confirmaron el daño neurológico y la pérdida celular en el putamen caudado. Se incrementó la inmunorreacción de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata , disminuyendo la inmunorreacción de la descarboxilasa del ácido glutámico en el globo pálido lateral de los animales isquémicos tratados con placebo; sin embargo, el tratamiento con atorvastatina pudo revertirla, lo que logró una disminución significativa de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata y aumentando los niveles de descarboxilasa del ácido glutámico en el globo pálido lateral. Conclusión. Nuestros datos sugieren que la atorvastatina en el tratamiento posterior a la isquemia ejerce neuroprotección en las zonas exofocales, modulando las poblaciones neuronales gabérgicas y dopaminérgicas del sistema nigroestriatal, lo que podría prevenir trastornos neurológicos.

Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease

There is a great concern in the literature for the development of neuroprotectant drugs to treat Parkinson's disease. Since anesthetic drugs have hyperpolarizing properties, they can possibly act as neuroprotectants. In the present study, we have investigated the neuroprotective effect of a mixture of ketamine (85 mg/kg) and xylazine (3 mg/kg) (K/X) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) rat models of Parkinson's disease. The bilateral infusion of MPTP (100 æg/side) or 6-OHDA (10 æg/side) into the substantia nigra pars compacta of adult male Wistar rats under thiopental anesthesia caused a modest (~67 percent) or severe (~91 percent) loss of tyrosine hydroxylase-immunostained cells, respectively. On the other hand, an apparent neuroprotective effect was observed when the rats were anesthetized with K/X, infused 5 min before surgery. This treatment caused loss of only 33 percent of the nigral tyrosine hydroxylase-immunostained cells due to the MPTP infusion and 51 percent due to the 6-OHDA infusion. This neuroprotective effect of K/X was also suggested by a less severe reduction of striatal dopamine levels in animals treated with these neurotoxins. In the working memory version of the Morris water maze task, both MPTP- and 6-OHDA-lesioned animals spent nearly 10 s longer to find the hidden platform in the groups where the neurotoxins were infused under thiopental anesthesia, compared to control animals. This amnestic effect was not observed in rats infused with the neurotoxins under K/X anesthesia. These results suggest that drugs with a pharmacological profile similar to that of K/X may be useful to delay the progression of Parkinson's disease.

LPS-induced degeneration of dopaminergic neurons of substantia nigra in rats / 华中科技大学学报（医学）（英德文版）

In order to investigate the neurotoxicity of lipopolysaccharide (LPS) on the dopaminergic neurons of substantia nigra and the pathogenesis of Parkinson disease, LPS was stereotaxically infused into substantia nigra (SN). At different dosages and different time points with 5 microg LPS, the damage of the dopaminergic neurons in SN was observed by using tyrosine-hydroxylase (TH) immunohistochemical staining. The results showed that 14 days after injection of 0.1 microg to 10 microg LPS into the rat SN, TH-positive (TH+) neurons in the SN were decreased by 5%, 15%, 20%, 45 %, 96% and 99% respectively. After injection of 5 microg LPS, as compared with the control groups, TH+ neurons began to decrease at 3rd day and obviously decrease at 14th day, only 5% of total cells, and almost disappeared 30 days later. The results suggested that LPS could induce the degeneration of dopaminergic neurons in the SN in a dose- and time-dependent manner.

Nightmares without atonia as an early symptom of diffuse Lewy bodies disease

A male 70 years old patient with diffuse or ''pure'' Lewy body disease is described. The diagnosis was made based on clinical features of nightmares with no atonia, attention deficits with fluctuation in cognitive function, incapacity to find his way around the neighbourhood and other formerly familiar environments and mild neuropsychiatric symptoms. Neuropsychological assessment showed memory deficits, visuospatial and visuo-constructive disturbances. He had neither parkinsonism nor recurrent visual hallucinations typically well formed and detailled. Neuroimaging (computed tomography and magnetic resonance spectroscopy) showed mild diffuse cortical atrophy, mostly on the left temporal lobe and a decrease of N-acetil-aspartate levels. A cholinesterase inhibitor was prescribed to this patient during 6 months with clinically relevant behavioral effect. Diagnosis confirmation was made by post-mortem neuropathological findings. Macroscopical features were mild atrophy on the frontal, parietal and temporal lobes, notedly on the frontal lobes. Microscopically, there was neuronal loss and diffuse classic Lewy bodies. Brainstem (substantia nigra, raphe nucleus, locus coeruleus, pedunculopontine nucleus), limbic cortex, and neocortex (frontal, parietal and temporal) were the areas of predilection for Lewy bodies. Hematoxylin-eosin and Bielschowsky staining did not show neuronal swelling (balooned cell), argyrophilic inclusion (Pick's bodies), neurofibrillary tangles nor senile plaques. Immunohistochemical staining for anti-tau, anti-beta-amyloid, and anti-prion protein were negative. Antiubiquitine reaction was positive for Lewy body in the cerebral cortex and brainstem

Protective effect of GSH on PD model induced by 6-OHDA in vitro / 华中科技大学学报（医学）（英德文版）

To study the effects of 6-hydroxydopamine (6-OHDA) and reduced glutathione (GSH) on the nigral dopaminergic neurons in brain slices in vitro, immolunohistochemical technique was used to observe the changes of TH-stained neurons, including cell bodies and the dendrites, in the substantia nigra (SN) of midbrain slices of rats after incubation for 1 h in the presence of GSH 15 min before and during the period of incubation with 6-OHDA. The results showed that cell bodies remained intact but dendrites were fragmented and truncated after treatment with 6-OHDA. The antioxidant GSH alone did not significantly affect the dendrites of SN neurons but prevented 6-O-HDA-induced damage of dendrites. It was concluded that glutathione may prevent 6-OHDA-induced dopaminergic neurodegeneration and play a protective role in dopaminergic neurons.