Evolution of the reticular formation

The reticular formation of mammals contains numerous nuclei which can be recognized by their projection patterns, cytoarchitectonics, and neuropeptide/neurotransmitter content. We have identified reticular nuclei in representatives from numerous reptilian groups and ascertained presence or absence of these reticular nuclei in an attempt to use neuronal occurrence as a tool to determine phylogenetic relationships. Recently these studies have been extended to two elasmobranchs, a galeomorph shark and a ray. In this report, we concentrate on three medullary spinal projecting reticular nuclei, reticularis gigantocellularis, reticularis magnocellularis, and reticularis paragigantocellularis. We found that all three nuclei were present in rats, lizards, and elasmobranchs, but one nucleus was absent in crocodilians, and two nuclei were absent in turtles. Thus brain organization may give us clues to phylogenetic relationships. Moreover, these three reticular nuclei exhibited remarkably similar cellular morphology in mammals, reptiles, and elasmobranchs.     

Mechanism of the effect of the midbrain reticular formation on the hypothalamus-hypophysis-thyroid gland system]

The role of the posterior hypothalamic nuclei in the transmission of the influences of the mesencephalic reticular formation upon the thyroid hormone secretion was studied. Stimulation of the mesencephalic reticular formation in anesthetized cats was followed by the excitation of the thyroid hormoone secretion: the content of the blood protein-bound iodine was increased. This effect was eliminated after the bilateral coagulation of the posterior hypothalamic nuclei. These findings confirmed the hypothesis on the leading role of the posterior hypothalamic nuclpeus in the stimulation of the hormone secretion.     

Advances in the clinical development of antiepileptic drugs

In this paper we describe advances in the clinical development of antiepileptic drugs as a function of the Antiepileptic Drug Development Program of the National Institute of Neurological and Communicative Disorders and Stroke. This program encompasses both the preclinical and clinical elements of drug development through the Anticonvulsant Screening Project, the Toxicology Project, and the support of controlled clinical trials of potential new drugs that emerge from these projects and promise to be more effective and less toxic than those currently available for the treatment of epilepsy.     

Determination of antiepileptic drugs in biological material

Current analytical methodologies applied to the determination of antiepileptic drugs in biological material are reviewed. The role of chromatographic techniques is emphasized. Special attention is focused on new chemical entities as well as current trends such as high-speed liquid chromatographic techniques, hyphenated techniques and electrochromatography techniques. A review with 542 references.     

Effects of different classes of antiepileptic drugs on brain-stem pathways

Antiepileptic drugs probably act by preventing the spread of the abnormal paroxysmal activity from the epileptogenic focus to surrounding normal neurons. An investigation of the mechanism of action of established anticonvulsant drugs on normal neuronal systems may therefore offer useful insights into the pathogenesis of the seizure disorders that these drugs serve to control. Antiabsence drugs (ethosuximide, valproate) depress reticular inhibitory pathways. Drugs effective against generalized tonic-clonic seizures (phenytoin, carbamazepine, valproate) depress reticular excitatory pathways. Drugs that are also effective against trigeminal neuralgia (phenytoin, carbamazepine) also depress afferent excitation and facilitate segmental inhibition in the trigeminal complex. Drugs that depress afferent excitation and facilitate segmental inhibition but do not depress the reticular system (baclofen) are effective against trigeminal neuralgia but do not have clinical antiepileptic properties. These observations indicate that the ability to depress the reticular core is an important characteristic of antiepileptic drugs, and suggest that the reticular core is involved in the spread and generalization of clinical seizures.     

Pharmacophore model for antiepileptic drugs acting on sodium channels

Fifteen antiepileptic drugs (AED), active against the maximal electroshock seizure test and able to block the neuronal voltage-dependent sodium channel, have been studied by means of a similarity analysis. Structural and electronic, quantum chemically derived characteristics are compared. Rigid analogs are included, because of the flexibility of some structures, in order to discern the conformational requirements associated with these ligands in the moment of the interaction. An inactive compound (ethosuximide) helps in the definition of the structural factors that are important for the activity. We propose a pharmacophore model that, giving an interpretation of the biological activity, allows the design of new AED with a well-defined mechanism of interaction.     

Inhibition of aquaporin 4 by antiepileptic drugs

The potential of antiepileptic drugs (AEDs) to inhibit the water transport properties of aquaporin 4 (AQP4) was investigated using a combination of in silico and in vitro screening methods. Virtual docking studies on 14 AEDs indicated a range of docking energies that spanned approximately 40 kcal/mol, where the most stabilized energies were consistent with that of the previously identified AQP4 inhibitor acetazolamide. Nine AEDs and one bio-active metabolite were further investigated in a functional assay using AQP4 expressing Xenopus oocytes. Seven of the assayed compounds were found to inhibit AQP4 function, while three did not. A linear correlation was indicated between the in silico docking energies and the in vitro AQP4 inhibitory activity at 20 microM.