Dale's principle was first proposed by Eccles in 1954 based on 3 lectures given by Dale in 1934 and 1952. Many authors in the literature define Dale's principle as the “one neuron-one transmitter concept”. The origin of such an idea, however, is rather vague. Neither Dale nor Eccles stated literally the one neuron-one transmitter concept. It seems now appropriate to define Dale's principle according to Eccles (1976) as follows: “at all the axonal branches of a neuron there is liberation of the same transmitter substance or substances”. Recent studies showed examples that are not in accord with the “one neuron-one transmitter concept”. Many cases were shown in which a neuron contains more than one transmitter. Whether this is a common rule or exceptional remains to be clarified by future studies.

View full abstract

Effects of lisuride, a central dopamine agonist of the ergot type, on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were studied using the autoradiographical ¹⁴C-iodoantipyrine and ³H-deoxyglucose method, respectively, in conscious rats. Lisuride significantly stimulated LCBF in the cerebellar gray matter. LCBF in some other regions including the cerebral cortex, caudate-putamen, thalamus, geniculate body and substantia nigra were also stimulated by lisuride. No changes were observed in the hippocampus, hypothalamus and white matter. A close correlation was observed between LCBF and LCGU. Region specificity of the stimulatory effect by lisuride on LCBF and LCGU was coincident. Lisuride shortened the lethal time in the anoxia model. In conclusion, lisuride stimulated not only glucose utilization but also blood flow in local regions of the brain.

View full abstract

Effects of continuous oral administration of Buflomedil on acetylcholine (ACh) and neuroactive amino acids contents and energy metabolism in the brain were investigated using Wistar Kyoto rat (WKY) and spontaneously hypertensive rat (SHR). In both WKY and SHR, continuous oral administration of Buflomedil (30 mg/kg × 7 days) had no effect on ACh content in all cerebral areas examined. On the other hand, continuous oral administration of Buflomedil to SHR induced a significant increase in the contents of glutamic acid and taurine in the striatum and hypothalamus, while it resulted in a significant decrease in the contents of glycine and taurine in the midbrain and hippocampus. Glucose and ATP contents in the striatum of SHR showed a significant increase following the continuous oral administration of Buflomedil. These results suggest that Buflomedil may be a drug capable of improving various neuropsychiatric symptoms associated with cerebrovascular insufficiency by modifying the content of neuroactive amino acids and accelerating energy metabolism in the brain.

View full abstract

The effects of a new tricyclic antidepressant quinupramine (5-(3-quinuclidinyl)-10, 11-dihydro-5H-dibenz [b, f] azepine) on various animal behaviors were examined in mice and rats and compared with those of imipramine, amitriptyline and maprotiline. Quinupramine antagonized haloperidol-induced catalepsy and tetrabenazine-induced ptosis and potentiated methamphetamine- and apomorphine-induced stereotyped behavior. These effects were almost the same as or even more potent than those of imipramine and amitriptyline. Quinupramine decreased locomotor activity in mice, but potentiated methamphetamine-induced hyperactivity to a greater degree than imipramine and amitriptyline. On the other hand, quinupramine inhibited muricide in accumbens-lesioned rats, but did not prominently inhibit muricide in olfactory-bulbectomized and raphe-lesioned rats. Quinupramine decreased the duration of immobility in low doses without affecting locomotor activity, and this effect was almost the same as that of imipramine and amitriptyline and more potent than that of maprotiline. Quinupramine antagonized physostigmine lethality and oxotremorine-induced tremor, suggesting that quinupramine has a central anticholinergic action. Quinupramine, like imipramine and amitriptyline, has no effect on conditioned avoidance behavior. In conclusion, quinupramine generally has the same behavioral profile as typical tricyclic antidepressants, but it has somewhat different effects from imipramine and amitriptyline since quinupramine has a potent central anticholinergic and a weak antimuricide effect.

View full abstract

The reactivity and specificity of commonly used non-steroidal anti-inflammatory drugs (NSAID) towards two major intracellular aspartic proteinases, cathepsins D and E, were investigated. Of the different drugs tested, indomethacin and flufenamic acid were shown to be potent inhibitors of cathepsin D. Sodium salicylate (SA) and aspirin also inhibited cathepsin D, although the apparent inhibition was observed at the concentrations of 5mM or above. The inhibitions by these drugs were pH-dependent. The maximal inhibitory potencies of indomethacin and aspirin against cathepsin D activity were observed at pH values below 4.0, whereas that of flufenamic acid was at pH values above 7.0. The Lineweaver-Burk plots showed that the inhibition of cathepsin D by these drugs was of a non-competitive type. On the other hand, all NSAID tested, except for SA, had no inhibitory effect on cathepsin E. SA alone inhibited cathepsin E at concentrations above 50mM. The inhibition of cathepsin E by SA was of the non-competitive type. Of the three monohydroxy benzoates, the inhibitory potency of the ortho isomer (SA) against cathepsin E was greater than those of the meta and para isomers.

View full abstract

Benexate·CD, a new orally active antiulcer agent, is an inclusion compound of benexate and β-cyclodextrin (β-CD). The present report investigated the significance of complex formation on the antiulcer activity of benexate, the effective ingredient of benexate·CD. To evaluate the improvement of solubility, the dissolution properties of benexate from various pharmaceutical forms into the 1st fluid of the Pharmacopoeia of Japan, a model of gastric juice, were compared. Benexate itself was hardly soluble, but the physical mixture of benexate and β-CD showed a solubility increase of benexate. On the other hand, benexate·CD showed a supersaturated dissolution curve and its peak concentration was 8 times higher than the solubility of the physical mixture. When benexate·CD was administered orally to pylorus ligated rats in the powder formulation, the similar supersaturated dissolution behavior was observed in the stomach, and the benexate level in gastric tissue was higher than that in benexate or the physical mixture administration. Benexate·CD extremely inhibited the ulcer formation caused by HCI-ethanol ingestion, but there was no significant inhibition after treatment with benexate or the physical mixture. These results indicated that it is necessary for benexate to form an inclusion compound in order to exert a strong antiulcer activity.

View full abstract

Inhibitory effects of cernitin pollen extract (CN-009), consisting of T-60 (a water-soluble extract) and GBX (an acetone-soluble extract) at a ratio of 20 : 1, were investigated in rat urethral smooth muscle and diaphragm. In the urethral smooth muscle, CN-009 (3.0×10^-4 ?? 3.0×10^-3 g/ml), T-60 and GBX (corresponding to CN-009) concentration-dependently inhibited the noradrenaline (NA, 10^-5 g/ml)-induced contraction. According to Bürgi's calculation, the inhibition by T-60 and GBX was synergistic. On the other hand, GBX inhibited the NA-contraction non-competitively and also inhibited the K⁺-contraction. In contrast, T-60 tended to inhibit competitively, but did not affect the K⁺-contraction. In the diaphragm, CN-009 (5.25×10^-3 ?? 2.1×10^-2 g/ml) concentration-dependently inhibited the nerve stimulation-induced twitch response. T-60 (corresponding to CN-009) showed no effect, while GBX slightly inhibited the twitch response. The effects of T-60 and GBX were synergistic. The inhibitory effects of CN-009 (2.1×10^-2g/ml) and GBX (1.0×10^-2 g/ml) were specific against the nerve stimulation and were not antagonized by neostigmine (1.0×l0-5 g/ml). These results suggested that these effects were neither musculotropic nor competitive against ACh. In conclusion, CN-009 concentration-dependently inhibited the urethral contraction and the skeletal muscular twitch response. It was suggested that T-60 and GBX had different mechanisms and inhibited the response synergistically.

View full abstract

Authors have reported that the oral potency ratio of AD-1590 to indomethacin varies with the animal models employed; the ratio is 4, 2.3 and 31 in the tests of acetic acid-induced vascular permeability (male mice), carrageenan hind paw edema (male rats) and UV-erythema (female guinea pigs), respectively. Thus, the relationship between the difference in the anti-inflammatory activity of AD-1590 among animal models and the species difference of the plasma AD-1590 level was investigated in experimental animals in order to ascertain the cause of the difference in the potency ratio. Inhibitory potency of AD-1590 on UV-erythema and increased vascular permeability induced by acetic acid in male rats was about 2.1 and 2.3 times, respectively, that of indomethacin. On the other hand, after a single oral administration of 5 mg/kg, the highest plasma AD-1590 level was seen in female guinea pigs (AUC_{0-8 hr}=68.1 μg·hr/ml) ; and followed by that in mice (male, 32.1; female, 36.1) > male dogs (11.5)≥rats (male, 9.02; female, 12.5), male rabbits (9.17) > male monkeys (9.34 at 6 mg/kg) . Hucker et al. have reported that the plasma level of indomethacin in rats is several times higher than that in guinea pigs, rabbits and monkeys. These results suggest that most of the species difference in the relative potency of AD-1590 to indomethacin in the anti-inflammatory activity results from the species difference in the plasma level of both drugs.

View full abstract