Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons

Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

ummary
By means of the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazol (PTZ) seizure threshold test, and the Rotorod minimal neurotoxicity test, the Anticonvulsant Screening Project has evaluated the activity of 1,495 experimental compounds accessioned in the first 2 years. A three-screen protocol for appraising these compounds has proved reliable, fast, and inexpensive. Preliminary data show that 430 of these compounds have good anticonvulsant activity. Completed evaluations of 352 identified 16 that have anticonvulsant activity at doses less than 75 mg/kg and protective indices greater than 5.0.

RESUME
El Proyecto de Seleccion de Anticonvulsivos ha valorado la actividad de 1,495 compuestos que han aparecido en los liltimos 2 anos mediante el test de electroshock maximo, el test de determinacion de umbral epileptico con la inyeccion subcutanea de pentilentetrazol y el test de Rotorod de minima neuro-toxicidad. Un protocolo de tres selecciones para valorar estos compuestos ha demostrado ser fiable, rapido y economico. Los resultados preliminares muestran que 430 de estos compuestos tienen buena actividad anticonvulsiva. Evaluaciones completas de 352 productos identificaron 16 que poseen actividad antiepileptica a dosis menores de 75 mg/kg e indice protectores mayores de 5.0.

RESUMEN
Le programme de depistage des medicaments anti-epileptiques (anticonvulsant screening project), base sur les deux tests des crises provoqudes chez l'animal par l'electrochoc et l'injection sous-cutanee de pentylenetetrazol et sur le test Rotorod de neurotoxicity minimale, a permis d'evaluer les propriety antiepileptiques de 1,495 produits experimentes pendant les deux premieres annees de son activite. Le protocole operatoire a trois niveaux ainsi utilise s'est avere sur, rapide et economique. Les donnees prdliminaires montrent que 430 de ces produits ont une bonne propridte anticonvulsive. Une Evaluation plus complete de 352 de ces produits a permis d'en identifier 16 qui presentent une propriete anticonvulsive a des doses inferieures a 75 mg/kg et qui possedent un indice de protection supdrieur a 5.0.

ZUSAMMENFASSUNG
Mit Hilfe des maximalen Elektroshock-Tests, des subkutanen Pentylentetrazol-Krampfschwellentests und des Rotorod minimalen Neurotoxizitats-Test wurden im Antikonvulsiva-Screening-Projekt in den ersten 2 Jahren die Aktivitat von 1,495 eingereichten Substanzen experimentell untersucht. Ein Drei-Raster-Protokoll zur Einschatzung dieser Substanzen wurde als durchfilhrbar, schnell und billig befunden. Die vorlaufigen Ergebnisse zeigen, das 430 dieser Substanzen gute antikonvulsive Wirkung haben. Die endgultige Beurteilung ergab, das 16 von 352 Substanzen eine antikonvulsive Wirkung bei Dosen unter 75 mg/kg und einen Schutzindex tiber 5.0 besitzen.

Antiepileptic drug development: II. Anticonvulsant drug screening.

Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice

The purpose of the present experiment was to examine the effectiveness of a modified rotarod test in detecting motor deficits following mild and moderate central fluid percussion brain injury. In addition, this investigation compared the performance of the rotarod task with two other commonly used measures of motor function after brain injury (beam-balance and beam-walking latencies). Rats were either injured with a mild (n = 14) or moderate (n = 8) level of fluid percussion injury or were surgically prepared but not injured (n = 8). All rats were assessed on all tasks for 5 days following their respective treatments. Results revealed that both the mild and moderate injury levels produced significant deficits in the ability of the animals to perform the rotarod task. Performance on the beam-balance and beam-walking tasks were not significantly impaired at the mild injury level. It was only at the moderate injury level that the beam-balance and beam-walking tasks detected deficits in motor perform...

The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury.

A note on a simple apparatus for detecting neurological deficit in rats and mice.

A homologous series of twenty basic esters of mono- and dialkylmalonic acid has been pharmacologically investigated. The preliminary testing included antispas-modic testing against spontaneous contractions, barium-induced spasms, and metha-choline-induced spasms of the isolated guinea pig ileum; local anesthetic testing employing the rabbit cornea and the guinea pig wheal; and anti-secretory testing employing pyloric ligation in the rat. The monobasic esters possess greater anti-spasmodic, local anesthetic, and antisecretory activity than the dibasic esters. Activity increased with the length of the side chains. The most active compound of the series is a more active spasmolytic than papaverine hydrochloride, is equal to the local anesthetic activity of cocaine hydrochloride, and is less active than atropine sulfate in inhibiting unstimulated gastric secretions.

The Pharmacological Activity of a Series of Basic Esters of Mono- and Dialkylmalonic Acids

A series of aralkylamine hydrochlorides has been shown to possess spasmolytic as well as some degree of local anesthetic activity. Compounds D-236 and D-244 are the most potent antispasmodics, haying 120 and 108.43% of the activity of papaverine as tested by their ability to inhibit the spontaneous contractions of guinea pig ileum. Both compounds possess approximately twice the activity of Pavatrine as tested on barium-induced spasms of the guinea pig ileum. Compound D-244 is the most toxic of the series (LD 50 , between 10 and 15 mg./Kg. in mice), and also the most irritant as tested on the rabbit eye as well as by the method of Kuna and Cuchie. Compounds D-236 and D-238 did not show an inhibition of unstimulated gastric secretions in rats at a dosage level of 10 mg./Kg.

A Pharmacological Study of a Series of Aralkylamines

An investigation was made of the effects of various factors and drugs on the total soluble nonprotein sulfhydryl content of rat liver. It was found that the combination of fasting, hydration, and bilateral tourniquets resulted in the lowest mg. % of the sulfhydryl content. Acetylsalicylic acid 500-600 mg./Kg., salicylamide 150 mg./Kg., and acetophenetidin 600 mg./Kg., inhibited the decrease of the total nonprotein sulfhydryl content in the liver of the rat subjected to stress. Sodium pheno-barbital 50 mg./Kg., and morphine sulfate 10 mg./Kg., also gave similar results. Aminopyrine 100-600 mg./Kg., and sodium salicylate 200-750 mg./Kg., failed to inhibit the decrease of sulfhydryl content of the stressed rat liver. At the large doses, both aminopyrine and sodium salicylate proved fatal to the animals tested. It was possible to demonstrate that sodium salicylate at the 200 mg./Kg. dose level caused a decrease of the sulfhydryl content without the use of tourniquets. This study indicates that the protection of the total nonprotein sulfhydryl content of the stressed rat liver is not of a high degree of specificity.

Comparative Effects of Certain Nonnarcotic Analgetics on the Pain-Induced Lowering of Total Nonprotein Sulfhydryl Content of Rat Liver*

Diphenic acid and sodium diphenate exhibited little or no action when tested for local anesthetic, antihistaminic, spasmolytic, and anticonvulsant activity. These compounds did not potentiate sodium pentobarbital-induced hypnosis alter, the p H, total volume or acidity of unstimulated gastric secretions or affect the blood pressure in rats. Acute toxicity shows sodium diphenate to be of slightly lesser toxicity than sodium benzoate. Histopathological examination of tissues and organs revealed no apparent alteration due to repeated dosage. Antibacterial and antifungal studies with diphenic acid and sodium diphenate showed no activity with concentrations as high as 20%. Intraperitoneal injections of sodium diphenate in rats enhanced urine flow significantly over controls. Practically all of the intraperitoneally injected sodium diphenate is excreted unchanged in the urine, but it is not absorbed when administered orally to rats.

T.S. Miya

Papers

A note on a simple apparatus for detecting neurological deficit in rats and mice.

The Pharmacological Activity of a Series of Basic Esters of Mono- and Dialkylmalonic Acids

A Pharmacological Study of a Series of Aralkylamines

Comparative Effects of Certain Nonnarcotic Analgetics on the Pain-Induced Lowering of Total Nonprotein Sulfhydryl Content of Rat Liver*

A pharmacologic study of diphenic acid and its sodium salt.