[Astragalus membranaceus promote expression of insulin-like growth factor 1 in rat model of olivo-cerebellar degeneration].

OBJECTIVE: To observe the effect of Astragalus membranaceus (AM) on insulin-like growth factor 1 (IGF-1) expression in a rat model of olivo-cerebellar degeneration and assess the neuroprotective actions of AM meanwhile. METHOD: Rats model of olivo-cerebellar degeneration was established by using 3-acetylpyridine. The effect of AM on the expression of Calbindin D-28K in inferior olive (IO) neurons by immunohistochemistry, the serum IGF-1 level by Elisa, the IGF-1 mRNA level in the cerebellum by RT-PCR were detected respectively. RESULT: AM effectively improve the serum IGF-1 level, Cerebellar IGF-1 mRNA level and the survival of the 10 neurons in a rat model of olivo-cerebellar degeneration, even at a lower dose (9 g x kg(-1)), and the effect was in a dose-dependent manner. CONCLUSION: AM could effectively upregulate the IGF-1 expression in the rat model of olivo-cerebellar degeneration, and have neuroprotective effect on IO neurons.

ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage.

Regulated necrosis has emerged as a major cell death mechanism in response to different forms of physiological and pharmacological stress. The AlkB homolog 7 (ALKBH7) protein is required for regulated cellular necrosis in response to chemotherapeutic alkylating agents but its role within a whole organism is unknown. Here, we show that ALKBH7 modulates alkylation-induced cellular death through a tissue and sex-specific mechanism. At the whole-animal level, we find that ALKBH7 deficiency confers increased resistance to MMS-induced toxicity in male but not female mice. Moreover, ALKBH7-deficient mice exhibit protection against alkylation-mediated cytotoxicity in retinal photoreceptor and cerebellar granule cells, two cell types that undergo necrotic death through the initiation of the base excision repair pathway and hyperactivation of the PARP1/ARTD1 enzyme. Notably, the protection against alkylation-induced cerebellar degeneration is specific to ALKBH7-deficient male but not female mice. Our results uncover an in vivo role for ALKBH7 in mediating a sexually dimorphic tissue response to alkylation damage that could influence individual responses to chemotherapies based upon alkylating agents.

[Antibiotics and gait disorders]. / Antibioticos y trastornos de la marcha.

The neurological toxicity of many antibiotics has been reported in a number of articles and clinical notes. In this review antibiotics are classified according to the physiopathogenic mechanism that can give rise to a gait disorder, taking both clinical and experimental data into account. An exhaustive search was conducted in Google Scholar and PubMed with the aim of finding reviews, articles and clinical cases dealing with gait disorders secondary to different antibiotics. The different antibiotics were separated according to the physiopathogenic mechanism that could cause them to trigger a gait disorder. They were classified into antibiotics capable of producing cerebellar ataxia, vestibular ataxia, sensitive ataxia or an extrapyramidal gait disorder. The main aim was to group all the drugs that can give rise to a gait disorder, in order to facilitate the clinical suspicion and, consequently, the management of patients.

TITLE: Antibioticos y trastornos de la marcha.La toxicidad neurologica de muchos antibioticos se ha documentado en numerosos articulos y notas clinicas. En esta revision se clasifican los antibioticos en funcion del mecanismo fisiopatogenico por el que pueden provocar un trastorno de la marcha, teniendo en cuenta tanto datos clinicos como experimentales. Se ha realizado una busqueda exhaustiva en Google Scholar y PubMed con el objetivo de encontrar revisiones, articulos y casos clinicos acerca de trastornos de la marcha secundarios a distintos antibioticos. Se han separado los diferentes antibioticos en funcion del mecanismo fisiopatogenico por el cual podrian producir una alteracion de la marcha. Se han clasificado en antibioticos capaces de producir ataxia cerebelosa, ataxia vestibular, ataxia sensitiva o un trastorno de la marcha extrapiramidal. El principal objetivo era agrupar todos los farmacos que pueden provocar un trastorno de la marcha, para facilitar la sospecha clinica y, en consecuencia, el tratamiento de los pacientes.

The stereo-specific effect of D-serine ethylester and the D-cycloserine in ataxic mutant mice.

Spinocerebellar ataxia is one of the most common neurological disorders. However, few therapeutics are effective for the treatment of this disorder. In the present study, we investigated the efficacy of d-serine ethylester and a related substance, d-cycloserine, as therapeutic agents for ataxia in a murine model. Both compounds are known to stereospecific modulate N-methyl-d-aspartate type glutamate receptors, and impaired glutamate-mediated signaling has been implicated in spinocerebellar ataxia. Using a microdialysis method, we found that intraperitoneal administration of d-serine ethylester increases the extracellular content of endogenous d-serine in the mouse cerebellum for at least 3 h. Maximum elevation of the extracellular d-serine was observed at 40 min after injection. An open-field study was used to assay the effect of the d-serine derivatives on movement and ataxia. In mice exhibiting cytosine arabinoside-induced ataxia, d-serine ethylester reduced the falling index in a dose-dependent manner. The effect of d-serine ethylester was stereo-specific in that l-serine ethylester had no effect on the falling index at the maximum doses tested, and was partially inhibited by 5,7-dichlorokynurenate, an antagonist that binds to the glycine-binding site. Locomotor activity was not changed by the d-serine ethylester treatment. d-cycloserine also significantly reduced the falling index of the mice. Both d-serine ethylester and d-cycloserine had longer lasting effects than other potential therapeutic reagents for ataxia. Growing evidence suggests the essential involvement of endogenous d-serine in mammalian brain function, and our results suggest that d-serine derivatives may represent an effective new therapeutic for the treatment of spinocerebellar ataxia.

Myelinated nerve fiber regeneration following organophosphorus ester-induced delayed neuropathy.

Chickens which developed organophosphorus ester-induced delayed neuropathy (OPIDN) due to a single oral dose of 360 mg/kg tri-ortho-tolyl phosphate were followed for up to 64 days following toxicant administration. Neuropathy was well developed by day 14. Progressive, marked but incomplete clinical improvement was observed between that time and day 49, associated with regenerative process was initially noted on day 16 at a distal, non-terminal level of the tibial nerve branch to the lateral head of the gastrocnemius muscle. One or more axonal sprouts were seen in bands of Büngner, but only one regenerated fiber per band myelinated and grew. By day 64 the nerves from treated hens closely resembled those from the controls. Myelinated nerve fiber degeneration was noted in distal regions of long spinal cord white matter tracts, but no subsequent regeneration was observed in this region. These studies indicate that in OPIDN there is a transient period of neuronal injury, and that damaged cells having peripherally directed neurites are likely able to undertake axonal regeneration.

MRI studies of the neurotoxic effects of L-2-chloropropionic acid on rat brain.

L-2-Chloropropionic acid (L-CPA) is selectively toxic to rat cerebellar granule cells; necrosis is first observed about 36 hours after administration of L-CPA (750 mg/kg p.o.) becoming more marked by 48 h. Parallel to the onset of cell death an increase in cerebellar water content and sodium concentration has been reported suggesting an oedematous reaction. In this study T(2)-weighted (T(2)WI) and diffusion weighted (DWI) imaging were used to detect the development of neuronal damage in the cerebellum of rats as a result of exposure to L-CPA. T(2)WI and DWI were not able to detect cerebellar abnormalities at 37 h post-dosing except for a slight swelling of the cerebellum. However, at 48 h post-dosing when cerebellar swelling and granule cell necrosis were marked, T(2)WI and DWI hyperintensities were observed in the cerebellum. Therefore, under the conditions of this study, MRI was not able to detect abnormalities in the cerebellum prior to the onset of the clinical signs of neurotoxicity or at the time of early histological changes. T(2)WI also suggested a marked increase in the amount of fluid in the ventricular system of rats 37 and 48 h after dosing; fluid accumulation was observed in all animals studied whether or not necrosis was detected. The occurrence of T(2)WI hyperintensity in the forebrain lead us to discover a new lesion in the habenular nucleus.

[Chronic phenytoin intoxication occurred below the toxic concentration in serum and its pathological findings].

We reported on autopsy case of chronic phenytoin intoxication with cerebellar degeneration. The serum concentration of phenytoin were always within nontoxic range. This patient was diagnosed as treatment resistant epilepsy with severe mental and physical disorders. The remarkable histological changes were confined to the cerebellum in autopsy. Those lesions were discontinuous and focal, on the basis of morphometrical study of Purkinje cells and granular cells. Furthermore, there was discrepancy between degeneration of Purkinje cell and granular layers, which has not been described before. This case underlines that toxic cerebellar degeneration could be induced even by low level of serum phenytoin in case of combined antiepileptic drug therapy. The measurement of the concentration of a drug or drugs per se is a mere postsign, therefore a patient should be carefully followed.

Neuroprotective effects of mesenchymal stem cell transplantation in animal model of cerebellar degeneration.

BACKGROUND: The cerebellum has been considered a key structure for the processes involved in sensorimotor integration ultimately leading to motor planning and execution of coordinated movement. Thus, motor deficits and behavioral changes can be associated with cerebellar degeneration. METHODS: Here, the chemical neurotoxin pyridine-2,3-dicarboxylic acid (quinolinic acid, QA) used to create partially cerebellar degeneration in adult Wistar rats suitable for use in stem cell transplantation studies. Stereotaxicaly administration of QA (0.2 mmol) in the right cerebellar hemisphere (folia VI) caused noticeable motor disturbance in all treated animals. Forty-eights hours after causing lesion, rat bone marrow-derived mesenchymal stem cells (MSCs) were transplanted into damaged cerebellar hemisphere. We investigated the role of MSC transplantation in forms of motor and non-motor learning that involves the cerebellum and its neuroprotective effects in Purkinje cells loss. RESULTS: CM-Dil labeling showed that the transplanted MSCs survived and migrated in the cerebellum 6 weeks after transplantation. The MSC-transplanted group showed markedly improved functional performance on the rotating rod test (P≤0.0001) and beam walking test (P≤0.0001) during 6 weeks compared with the controls. For non-motor learning, we used passive avoidance learning test in 3 weeks after transplantation. The results showed that MSC transplantation prevented the development of memory deficit caused by cerebellar degeneration (P≤0.001). Stereological analysis in 6 weeks after transplantation showed that QA significantly decreases Purkinje cells in vehicle-treated rats and MSC transplantation is neuroprotective and decreases Purkinje cell loss in MSC-treated rats (P≤0.0001). CONCLUSION: The results indicate that transplantation of MSCs can significantly reduce the behavioral and neuroanatomical abnormalities of these animals during 6 weeks after engraftment. According to results of this assay, cell therapy by means of bone marrow-derived adult stem cells promises for treatment of cerebellar diseases.

Diffusion tensor MRI and fiber tractography of cerebellar atrophy in phenytoin users.

PURPOSE: The usefulness of diffusion tensor magnetic resonance imaging (DT-MRI) is still in debate, and the development of clinically feasible scan protocol is encouraged. The purpose of this study was to investigate the afferent fiber system to the cerebellum in patients with phenytoin (PHT)-induced cerebellar atrophy in comparison with cerebellar atrophy of other etiologies by using DT-MRI. METHODS: Thirteen patients (M/F ratio, 7:6; mean age, 42.5 years) and age-matched normal controls (n = 8) participated in this study. The patient group consisted of epilepsy patients who had received PHT therapy (n = 9) and clinically diagnosed as having olivopontocerebellar atrophy (OPCA; n = 4). DT-MRI was performed by using diffusion weighting of b = 600 s/mm2, and fractional anisotropy (FA) and color-coded vector maps were generated. FA of the middle cerebellar peduncle (MCP), the cerebellum, and transverse pontine fibers (TPF) was measured and compared between PHT and OPCA patients. RESULTS: Normal subjects showed FA values of 0.81 +/- 0.07 in MCP, 0.69 +/- 0.04 in TPF, and PHT users showed FA values of 0.84 +/- 0.09 in MCP, 0.72 +/- 0.08 in TPF, and 0.21 +/- 0.04 in cerebellum. OPCA patients showed FA values of 0.39 +/- 0.11 in MCP, 0.46 +/- 0.12 in TPF, and 0.22 +/- 0.07 in cerebellum. PHT users showed a statistically significant reduction of FA only in cerebellum, whereas OPCA demonstrated significant decrease of FA in MCP, TPF, and cerebellum (one-way analysis of variance, p < 0.01). Three-dimensional reconstruction of fiber tracts demonstrated decreased volume and altered fiber integrity within the peduncles and transverse pontine fibers in the OPCA group, whereas fiber course patterns in PHT users were similar to those in controls. CONCLUSIONS: PHT users showed normal orientation and anisotropy of MCP and TPF, whereas OPCA demonstrated impaired values, suggesting that PHT directly affects the cerebellum. DT-MRI can demonstrate detailed fiber configurations in degenerative diseases of brainstem and cerebellum and provides insight into the pathomechanisms of cerebellar atrophy.