Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy.

Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.

Efficacy of dapsone administered alone or in combination with diazepam to inhibit status epilepticus in rats.

Status epilepticus (SE) is a serious medical condition, as it may trigger epileptogenesis. SE produces continuous generalized seizures resulting in irreversible brain damage. Therefore, the use of neuroprotective agents to prevent cell damage, may reduce the impact of SE. The use of diazepam (DZP), has shown limited neuroprotective effect in SE patients. According to previous reports, dapsone (DDS) is able to reduce both cell damage and seizures, when administered 30 min before the onset of seizures. This study is aimed to evaluate the ability of DDS, alone or in combination with DZP starting their administration once the SE is onset to evaluate the control of seizures in rats. Results showed a reduced convulsive electrical activity after 30 min, 1 and 2 h after SE induced by kainic acid (KA) administration, in the animals treated with DZP alone or in combination with DDS. At 24 h, we observed electrical activity similar to baseline in all groups receiving treatment. The animals treated with DDS and DZP alone or in combination showed an increase in the number of viable pyramidal cells but only the combination showed a lower number of damaged pyramidal neurons of hippocampal CA3. In conclusion, DDS plus DZP was able to control SE and to prevent SE-induced damage, when administered in combination with DZP. As DDS is already in use for patients with leprosy, that combination may be a safe, good option for human cases of SE.

Transforming growth factor-ß1 may be a key mediator of the fibrogenic properties of neural cells in leprosy.

Fibrosis is the main cause of irreversible nerve damage in leprosy. Phenotypic changes in Mycobacterium leprae (ML)-infected Schwann cells (SCs) have been suggested to mediate this process. We found that SC line cultures stimulated with ML upregulated transforming growth factor-ß1 (TGF-ß1), and that TGF-ß1 or ML induced increased numbers of α-smooth muscle actin (α-SMA)-positive cells with characteristic stress fibers. Mycobacterium leprae and TGF-ß1 also induced increased type I collagen and fibronectin mRNA and secretion and augmented mRNA levels of SOX9 and ZEB1, which are involved in the epithelial-mesenchymal transition. These effects could be inhibited by the TGF-ß1 type I receptor (ALK5) inhibitor, SB-431542. In nerve biopsies from leprosy-infected patients with varying grades of fibrosis (n = 11), type I and III collagen and fibronectin were found in the endoneurium and perineurium, α-SMA-positive cells filled the fibrotic perineurium but not the endoneurium, and CD34-positive fibroblasts predominated in the endoneurium. Results of transcriptional studies of 3 leprosy nerves and 5 controls were consistent with these data, but α-SMA and other mRNA levels were not different from those in the control samples. Our findings suggest that TGF-ß1 may orchestrate events, including reprogramming of the SC phenotype, leading to transdifferentiation, connective tissue cell expansion, and fibrogenesis in the evolution of leprosy nerve lesions during some evolutionary stages.

Rifampicin protects PC12 cells against MPP+-induced apoptosis and inhibits the expression of an alpha-Synuclein multimer.

The potential cytoprotective effects of the anti-leprosy antibiotic rifampicin were investigated in rat pheochromocytoma (PC12) cells prior to intoxication with 1-Methyl-4-phenyl pyridinium (MPP(+)). MPP(+) induced both apoptotic and necrotic cell death, and increased the expression of a 57 kDa species of alpha-Synuclein. This species of alpha-Synuclein is larger than the monomer, and is therefore an oligomer or an aggregated form of the protein. Rifampicin significantly increased survival of these catecholaminergic cells in a concentration-dependent manner. The expression of the higher molecular mass alpha-Synuclein was increased by MPP(+) exposure, and its expression was inversely related to cell survival in the rifampicin-treated cells. Importantly, rifampicin suppressed apoptosis almost completely, without shifting the death cascade to necrosis, which is a problem that has been reported with caspase inhibitors of apoptosis (Hartmann, A., Troadec, J.D., Hunot, S., Kikly, K., Faucheux, B.A., Mouatt-Prigent, A., Ruberg, M. Agid, Y., Hirsch, E.C., 2001. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J. Neurosci. 21, 2247-2255). These results suggest that rifampicin improves survival of catecholamine- and alpha-Synuclein-containing cells, which degenerate in Parkinson's disease (PD), and thus may be therapeutic in this disease.

Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro.

Rifampicin is an antibacterial drug which is highly effective in the treatment of tuberculosis and leprosy. It has been shown to exert antioxidative as well as anti-apoptotic effects. In this study, the neuroprotective effect of rifampicin was examined after 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic cell death in vitro, and on the survival of retinal ganglion cells after optic nerve transection in vivo. Rifampicin administration significantly increased the number of surviving dopaminergic neurons after MPP+ intoxication as compared to control cultures. No cytotoxic effects were noted even at final rifampicin concentrations of 100 microM. In the rifampicin-treated group, retinal ganglion cell survival was significantly increased after axotomy as compared with vehicle-treated and phosphate-buffered saline-treated control animals. These results suggest that rifampicin is able to prevent neuronal degeneration in cell death paradigms involving oxidative stress and activation of apoptotic pathways. It may thus play a role in the future treatments of neurodegenerative disorders.

Alzheimer's disease and inflammation: a review of cellular and therapeutic mechanisms.

1. Of the neurodegenerative diseases that cause dementia, Alzheimer's disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology. 2. The senile plaques of AD consist primarily of complexes of the beta-amyloid protein. This protein is central to the pathogenesis of the disease. 3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. beta-Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin. 4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti-inflammatory drugs. Longitudinal studies have shown that the consumption of anti-inflammatory medications reduces the risk of AD only in younger patients (< 75 years). 5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non-steroidal anti-inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD. 6. Cyclo-oxygenase 2 enzyme is constitutively expressed in neurons and is up-regulated in degenerative brain regions in AD. Non-steroidal anti-inflammatory drugs may reduce this expression. 7. Platelets are a source of beta-amyloid and increased platelet activation and increased circulating beta-amyloid have been identified in AD. Anti-platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences. 8. Increased levels of luminal beta-amyloid permeabilizes the blood-brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti-inflammatory medications may alleviate these problems.

Post-traumatic migration and emergence of a novel cell line upon the ependymal surface of the third cerebral ventricle in the adult mammalian brain.

This investigation describes the migration and emergence of significant numbers of what appear to be neuron-like cells upon the surface of the median eminence of the adult rodent neurohypophyseal system of the endocrine hypothalamus following the trauma of hypophysectomy. These cells appear to migrate through the neuropil of the underlying median eminence and emerge in large numbers upon the surface of the third cerebral ventricle within 7 days following hypophysectomy (axotomy) of supraoptic (SON) and paraventricular neurites (PVN) of the adult neurohypophyseal system. Previous investigations have demonstrated regeneration of the neural stem and neural lobe in a variety of mammalian species (Adams et al., J Comp Neurol, 1969;135:121-144; Beck et al., Neuroendocrinology, 1969;5:161-182; Scott et al., Exp Neurol, 1995;131-1:23-39; Scott and Hansen, Vir Med 1997;124:249-261). It also has been demonstrated that the process of regeneration is invariably accompanied by the up-regulation of nitric oxide synthase (NOS), the enzyme that catalyzes arginine to nitric oxide (NO) and that both neurohypophyseal regeneration, as well as migration and emergence of neuron-like cells upon the surface of the adjacent third cerebral ventricle, is associated with the up-regulation of NOS and increased expression of NO. It also has been amply demonstrated that this entire process of neurohypophyseal regeneration and cell migration is completely inhibited by the introduction of the antagonist of nitric oxide, namely, nitroarginine (Scott et al., Exp Neurol, 1995;131-1:23-39; Scott and Hansen, Vir Med, 1997;124:249-261). The emergence and migratory dynamics of this novel cell line upon the floor of the rodent third cerebral ventricle are discussed with respect to the role of the ubiquitous free radical NO and the implications and potential clinical applications of neuronal migration following trauma in the human central nervous system (CNS).

No effect of anti-leprosy drugs in the prevention of Alzheimer's disease and beta-amyloid neurotoxicity.

There is continuing controversy as to whether or not anti-leprosy drugs prevent Alzheimer's disease (AD). Therefore, we examined the effect of anti-leprosy drugs on the prevalence of AD in leprosy patients, and also investigated the effect of anti-leprosy drugs on amyloid beta-protein (Abeta)-induced neurotoxicity in vitro. The present study suggests that anti-leprosy treatments do not prevent the onset of AD. None of our data found anti-leprosy drugs (dapsone, rifampicin, clofazimine, minomycin or ofloxacin) had any effect on Abeta neurotoxicity. It is now important to examine the infection of Mycobacterium leprae in the central nervous system to clarify the reason for the low prevalence of senile dementia, and low frequency of Abeta deposition in leprosy patients.

[Pharmacological basis of the action of isaxonine (author's transl)]. / Bases pharmacologiques de l'action de l'isaxonine.

The author reviews previous therapeutic attempts to stimulate regeneration of peripheral nerves. Since 1971 he has been studying a synthetic compound, isaxonine, which in rats accelerates nerve regeneration and functional recovery. Stimulation of axonal regeneration and collateral sprouting has been demonstrated in tissue cultures. The therapeutic activity of the compound has been demonstrated in man in leprous neuropathy and in vincristine neuropathy. Isaxonine has specific affinity for peripheral nerves. Its acts directly on the neuron or indirectly by stimulating production of a growth factor remains unknown. In vitro and in vivo studies isaxonine have shown that isaxonine antagonizes the noxious effects of Vinca alkaloids on neurotubular structure. Research in progress suggest a possible action of this new compound in other diseases related to tubulin anomaly.