Complex time-dependent alterations in the brain expression of different drug efflux transporter genes after status epilepticus.

Purpose: Frequent epileptic seizures or prolonged seizure activity (status epilepticus, SE) is known to increase the brain expression of drug efflux transporter genes and proteins, such as P-glycoprotein (Pgp) and members of the multidrug resistance protein (MRP) family, which might reduce brain levels of antiepileptic drugs and, therefore, be involved in drug resistance. However, the time course of alterations in Pgp or MRPs after seizures or SE is only incompletely known.

Methods: This prompted us to study the time course of alterations in the expression of different efflux transporter genes (Mdr1a, Mdr1b, MRP1, MRP2, MRP5) at various times after a pilocarpine-induced SE in limbic brain regions, using quantitative real-time polymerase chain reaction (RT-PCR) (qPCR).

The effects of FGF-2 gene therapy combined with voluntary exercise on axonal regeneration across peripheral nerve gaps.

Studies were conducted to determine the possibility that voluntary exercise could enhance regenerative effects of gene therapy via Schwann cells (SC) over-expressing FGF-2. Sedentary or exercise rehabilitation conditions were therefore provided shortly after reconstructing 10mm sciatic nerve gaps in rats with silicone grafts. Exercise for 7 days elevated mRNA levels of regeneration associated proteins (GAP-43 and synapsin I) in lumbar spinal cord and dorsal root ganglia of SC transplanted, in contrast to non-cellular reconstructed rats.

Increase in antiepileptic efficacy during prolonged treatment with valproic acid: role of inhibition of histone deacetylases?

Valproic acid (VPA) is a major antiepileptic drug (AED) with efficacy against multiple seizure types. It has a rapid onset of action but its anticonvulsant activity increases during prolonged treatment, which cannot be explained by drug or metabolite accumulation in plasma or brain. Among numerous other effects on diverse drug targets, VPA is an inhibitor of histone deacetylases (HDACs) that are involved in modulation of gene expression.

Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice.

Psychiatric disorders frequently occur in patients with epilepsy, but the relationship between epilepsy and psychopathology is poorly understood. Frequent comorbidities in epilepsy patients comprise major depression, anxiety disorders, psychosis and cognitive dysfunction. Animal models of epilepsy, such as the pilocarpine model of acquired epilepsy, are useful to study the relationship between epilepsy and behavioral dysfunctions.

Gene therapy in peripheral nerve reconstruction approaches.

Gene transfer to a transected peripheral nerve or avulsed nerve root is discussed to be helpful where neurosurgical peripheral nerve reconstruction alone will not result in full recovery of function. Axonal regeneration is supposed to be facilitated by this new therapeutic approach via delivery of specific regeneration promoting molecules as well as survival proteins for the injured sensory and motor neurons. Therefore gene therapy aims in long-term and site-specific delivery of those neurotrophic factors.

Perazine and carbamazepine in comparison to olanzapine in schizophrenia.

Atypical antipsychotics like olanzapine are more efficacious in treating negative symptoms and have less side effects. Nevertheless, important adverse effects of olanzapine are, for example, weight gain and hyperglycemia. Perazine in combination with carbamazepine has shown satisfying results in several single-schizophrenia patients, leading to the hypothesis of being equal or even superior to atypical antipsychotic monotherapy.

Marked differences in response to dopamine receptor antagonism in two rat mutants, ci2 and ci3, with lateralized rotational behavior.

We have recently described two rat mutants, ci2 and ci3, in which abnormal lateralized rotational behavior and locomotor hyperactivity occur either spontaneously or in response to external stimuli, such as new environment. While cochlear and vestibular defects are found in ci2 rats, ci3 rats do not exhibit any inner ear abnormalities. Both mutants show abnormal lateralities in striatal dopamine and in the density of dopaminergic neurons in substantia nigra or ventral tegmental area, which may be involved in the behavioral phenotype of these rats.

The pharmacokinetics of antiepileptic drugs in rats: consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy.

Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period.

Drug resistance in brain diseases and the role of drug efflux transporters.

Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders.

Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: a clinical pilot study.

A new antiepileptic and anxiolytic drug, ELB138, was evaluated in a clinical pilot study in dogs with newly diagnosed or chronic idiopathic epilepsy. The purpose was to verify clinically the anticonvulsant effectiveness of this substance, which had already been demonstrated experimentally. Data from 29 dogs treated with ELB138 were compared with results obtained retrospectively from 82 dogs treated with conventional antiepileptic medication.