Medial-tonsillar telovelar approach for resection of a superior medullary velum cerebral cavernous malformation: anatomical and tractography study of the surgical approach and functional implications.

BACKGROUND: Superior medullary velum cerebral cavernous malformations pose a challenge in terms of appropriate microsurgical approach. Safe access to this deep location as well as preservation of surrounding anatomical structures, in particular the superior cerebellar peduncle just lateral to the superior medullary velum and the dentate nuclei, is paramount to achieve a good functional outcome. METHODS: Cadaveric dissections provide useful knowledge of the normal anatomy while tractography allows a better understanding of the individual anatomy in the presence of a lesion. The medial-tonsillar telovelar approach provides a feasible corridor for accessing superior velum cerebral cavernous malformations without compromising the fibres contained in the superior cerebellar peduncle. The major cerebellar efferents-cerebello-rubral, cerebello-thalamic and cerebello-vestibular tracts-and afferents, anterior spinocerebellar, tectocerebellar and trigeminocerebellar tracts, within the superior cerebellar peduncle are preserved, and the dentate nuclei are not affected. RESULTS AND CONCLUSION: A retraction-free exposure through this natural posterior fossa corridor allows the patient with the anatomical and functional subtract to make a good functional recovery by minimizing the risk of a superior cerebellar syndrome, ataxia, tremor and dysmetria; decomposition of movement in the ipsilateral extremities, nystagmus and hypotonia; or akinetic mutism, reduced or absent speech with onset within the first post-operative week.

Garcinia kola aqueous suspension prevents cerebellar neurodegeneration in long-term diabetic rat - a type 1 diabetes mellitus model.

ETHNOPHARMACOLOGICAL RELEVANCE: The development of compounds able to improve metabolic syndrome and mitigate complications caused by inappropriate glycemic control in type 1 diabetes mellitus is challenging. The medicinal plant with established hypoglycemic properties Garcinia kola Heckel might have the potential to mitigate diabetes mellitus metabolic syndrome and complications. AIM OF THE STUDY: We have investigated the neuroprotective properties of a suspension of G. kola seeds in long-term type 1 diabetes mellitus rat model. MATERIALS AND METHODS: Wistar rats, made diabetic by single injection of streptozotocin were monitored for 8 months. Then, they were administered with distilled water or G. kola oral aqueous suspension daily for 30 days. Body weight and glycemia were determined before and after treatment. After sacrifice, cerebella were dissected out and processed for stereological quantification of Purkinje cells. Histopathological and immunohistochemical analyses of markers of neuroinflammation and neurodegeneration were performed. RESULTS: Purkinje cell counts were significantly increased, and histopathological signs of apoptosis and neuroinflammation decreased, in diabetic animals treated with G. kola compared to diabetic rats given distilled water. Glycemia was also markedly improved and body weight restored to non-diabetic control values, following G. kola treatment. CONCLUSIONS: These results suggest that G. kola treatment improved the general condition of long-term diabetic rats and protected Purkinje cells partly by improving the systemic glycemia and mitigating neuroinflammation.

Cerebellar cortical infarct cavities and vertebral artery disease.

INTRODUCTION: Cerebellar cortical infarct cavities are a newly recognised entity associated with atherothromboembolic cerebrovascular disease and worse physical functioning. We aimed to investigate the relationship of cerebellar cortical infarct cavities with symptomatic vertebrobasilar ischaemia and with vascular risk factors. METHODS: We evaluated the MR images of 46 patients with a recent vertebrobasilar TIA or stroke and a symptomatic vertebral artery stenosis ≥50 % from the Vertebral Artery Stenting Trial (VAST) for the presence of cerebellar cortical infarct cavities ≤1.5 cm. At inclusion in VAST, data were obtained on age, sex, history of vertebrobasilar TIA or stroke, and vascular risk factors. Adjusted risk ratios were calculated with Poisson regression analyses for the relation between cerebellar cortical infarct cavities and vascular risk factors. RESULTS: Sixteen out of 46 (35 %) patients showed cerebellar cortical infarct cavities on the initial MRI, and only one of these 16 patients was known with a previous vertebrobasilar TIA or stroke. In patients with symptomatic vertebrobasilar ischaemia, risk factor profiles of patients with cerebellar cortical infarct cavities were not different from patients without these cavities. CONCLUSION: Cerebellar cortical infarct cavities are seen on MRI in as much as one third of patients with recently symptomatic vertebral artery stenosis. Since patients usually have no prior history of vertebrobasilar TIA or stroke, cerebellar cortical infarct cavities should be added to the spectrum of common incidental brain infarcts visible on routine MRI.

Modulation of angiogenic factor VEGF by DNA-hsp65 vaccination in a murine CNS tuberculosis model.

Tuberculosis (TB) is a serious public health problem. Development of experimental models and vaccines are essential to elucidate physiopathological mechanisms and to control the disease. Vascular endothelial growth factor (VEGF) is a potent activator of vascular permeability and angiogenesis. VEGF seems to participate in breakdown of the blood brain-barrier (BBB) in tuberculous meningitis (TBM), contributing to worsening of disease. Therefore, the objective here was to extent the characterization of our previously described murine model of central nervous system TB (CNS-TB) by describing the VEGF participation in the CNS disease, and suggesting a vaccination plan in mice. Plasmid encoding DNA protein antigen DNA-hsp65 has been described as a protector against TB infection and was used here to test its effectiveness in the prevention of VEGF production and TB disease. Vaccinated mice and its controls were injected with Mycobacterium bovis bacillus Calmette-Guerin (BCG) in cerebellum. Four weeks after BCG injection, mice were perfused and brains were paraffin-embedded for VEGF expression analysis. We observed VEGF immunohistochemical expression in TBM and granulomas in non-vaccinated mice. The DNA-hsp65 treatment blocked the expression of VEGF in mice TBM. Therefore, our murine model indicated the VEGF participation in the physiopathology of CNS-TB and the potential prevention of the DNA-hsp65 in the disease progression.

Partial neuroprotection by 17-ß-estradiol in neonatal γ-irradiated rat cerebellum.

Acute and long-term complications can occur in patients receiving radiation therapy. It has been suggested that cytoprotection might decrease the incidence and severity of therapy-related toxicity in these patients. Developing cerebellum is highly radiosensitive and for that reason it is a useful structure to test potential neuroprotective substances to prevent radiation induced abnormalities. Recent studies have shown that estrogen can rapidly modulate intracellular signalling pathways involved in cell survival. Thus, it has been demonstrated that estrogens mediate neuroprotection by promoting growth, cell survival and by preventing axonal pruning. The aim of this work was to evaluate the effect of the treatment with 17-ß-estradiol on the motor, structural and biochemical changes induced by neonatal ionizing radiation exposure, and to investigate the participation of nitric oxide and protein kinase C, two important intracellular messengers involved in neuronal activity. Our results show that perinatal chronic 17-ß-estradiol treatment partially protects against radiation-induced cerebellar disorganization and motor abnormalities. PKC and NOS activities could be implicated in its neuroprotective mechanisms. These data provide new evidence about the mechanisms underlying estrogen neuroprotection, which could have therapeutic relevance for patients treated with radiotherapy.

Neuroprotective role of heme-oxygenase 1 against iodoacetate-induced toxicity in rat cerebellar granule neurons: Role of bilirubin.

Heme oxygenase (HO) catalyses the breakdown of heme to iron, carbon monoxide and biliverdin, the latter being further reduced to bilirubin. A protective role of the inducible isoform, HO-1, has been described in pathological conditions associated with the production of reactive oxygen species (ROS). The aim of this study was to investigate the role of HO-1 in the neurotoxicity induced by iodoacetate (IAA) in primary cultures of cerebellar granule neurons (CGNs). IAA, an inhibitor of the glycolysis pathway, reduces cell survival, increases ROS production and enhances HO-1 expression in CGNs. Furthermore, the induction of HO-1 expression by cobalt protoporphyrin (CoPP) prevented cell death and ROS production induced by IAA, whereas the inhibition of HO activity with tin mesoporphyrin exacerbated the IAA-induced neurotoxicity. The protective effect elicited by CoPP was reproduced by bilirubin addition, suggesting that this molecule may be involved in the protective effect of HO-1 induction in this experimental model.

Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice.

Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-1-propanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased falling latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg-exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon was completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer>Purkinje cells>molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex.

Delineating and understanding cerebellar neuroprotective pathways: potential implication for protecting the cortex.

The cerebellum is a brain region that is resistant to many of the neurodegenerative disorders such as stroke and Alzheimer's disease. In contrast, the neocortex (cerebrum, cerebral cortex) is vulnerable to these disorders. While there may be many reasons for the differences in vulnerability to acute and chronic neurodegenerative disorders, the cerebellum appears to be equipped with the tools necessary to protect itself against these types of insults. Over the last century, evidence has accumulated to suggest that the cerebellum is also involved in memory and higher cognitive function. We have discovered that intrinsic survival pathways exist in cerebellar granule cells that are regulated by low level stimulation of N-methyl-d-aspartate (NMDA) receptors. Activation of NMDA receptors protects vulnerable neurons against glutamate-mediated excitotoxicity acting on NMDA receptors. This report focuses on how modulation of neuronal survival by NMDA receptors through a brain-derived neurotrophic factor (BDNF)-mediated pathway may be incorporated into a network of cerebellar function, particularly in light of recent findings suggesting that the cerebellum plays a vital role in learning, memory, fear conditioning, and cognitive processing.

BAPTA-AM and ethanol protect cerebellar granule neurons from the destructive effect of the weaver gene.

The mechanisms by which the weaver gene (Reeves et al., 1989; Patil et al., 1995) inhibits neurite extension and/or induces death of the granule neurons in homozygous weaver mouse cerebellum are not presently understood. Here we show that BAPTA-AM and ethanol, which either reduce cytosolic levels of free calcium or prevent calcium entry, promote neurite outgrowth of the weaver neurons similar to the L-type calcium channel blocker verapamil (Liesi and Wright, 1996). Importantly, BAPTA-AM, ethanol, and verapamil not only restore neurite outgrowth of the weaver neurons but adjust their depolarized resting membrane potentials to the levels of normal neurons. These results indicate that calcium-dependent mechanisms mediate the action of the weaver gene and that the weaver neurons can be normalized by blocking this calcium effect. We further report that BAPTA-AM and verapamil also have a neuroprotective effect on normal neurons exposed to high concentrations of ethanol. We suggest that verapamil should be evaluated as a drug for treatment of alcohol-induced brain damage and neurodegenerative disorders.

Mode of prevention by phototherapy of cerebellar hypoplasia in a new Sprague-Dawley strain of jaundiced Gunn rats.

Postnatal changes in cerebellar wet weight and the effect of phototherapy were studied using a new strain of Gunn rats with a genetic background of the Sprague-Dawley strain (SDGR). The cerebellar wet weight of homozygous rats reached a maximum at postnatal day 10 and then it gradually decreased up to day 20, suggesting that the cerebellar hypoplasia of the rats was a consequence both of cellular underdevelopment and degeneration. Histological examinations of the 10 cerebellar lobules showed that lobules I-VIII of homozygotes were severely damaged while lobules IX and X were less affected, coinciding with previous reports of Wistar strain Gunn rats. Photoirradiation with blue light of homozygous rats from day 1 through 15 markedly improved their cerebellar development, and the cerebellar wet weight of these rats was almost comparable to that of heterozygous rats as examined at day 30. Photoirradiation from day 1 to 5 protected, though not fully, lobules I-V and VIII against damage, but not lobules VI and VII at all. Photoirradiation from day 6 to 10 prevented all the lobules from hypoplasia. Irradiation from day 11 to 15 was effective only at the tips of lobules VI and VII. These results indicate that the cerebellar hypoplasia of jaundiced Gunn rats can be effectively prevented by a series of photoirradiation during a particular period after birth and also that the most effective period is different among the lobules.

Prevention of virus-induced cerebellar diseases by defective-interfering lymphocytic choriomeningitis virus.

Defective-interfering (DI) lymphocytic choriomeningitis virus (LCMV) prevented disease in the central nervous system produced by standard LCMV. Standard LCMV injected into Lewis rats two days after birth produced a disorder distinguishable clinically by weight loss and ataxia and histologically by infiltration of mononuclear cells and necrosis of the cerebellum. Concurrent injection of DI LCMV with standard LCMV prevented the disease and markedly reduced the synthesis of standard LCMV and of viral antigens in the brain. Because inhibition of viral synthesis occurred early (day 3) after infection and because no interferon activity could be demonstrated, it was concluded that the interference effect was likely due to DI virus-mediated homologous interference. Other experiments showed that DI LCMV blocked viral antigen synthesis in culture. The curtailed production of viral antigens and cytolytic standard virus by DI virus may play a role in control of acute and persistent viral infections.