1. Pentobarbital (PTB) is metabolised by cytochrome P450 (CYP) enzymes, being a model compound for evaluating CYP-mediated drug-drug interactions, has become difficult to obtain for animal studies in Japan. The metabolic pathway of thiopental (TP), a barbiturate with similar pharmacological properties, remains insufficiently characterised. This study investigated TP metabolic profile, with emphasis on CYP modulator-induced drug-drug interactions.2. TP was administered intraperitoneally to either phenobarbital (PB), chloramphenicol (CP)-pretreated, or untreated rats. Plasma TP concentrations were quantified using HPLC-DAD and a plate reader. Hypnotic and sedative properties were assessed by time to loss of righting reflex and recovery from hindlimb paralysis. TP metabolism was further evaluated in vitro using rat liver microsomes (RLMs) and recombinant CYP enzymes, and hepatic CYP mRNA levels were quantified by real-time RT-PCR.3. Compared with TP alone, PB pretreatment shortened TP-induced anaesthesia and decreased plasma TP concentrations, whereas CP pretreatment prolonged the duration of action and increased plasma TP levels. TP metabolism was mediated by CYP2B1 and CYP2C11. PB pretreatment induced CYP2B1 and enhanced TP metabolism, whereas CP pretreatment suppressed CYP2C11, inhibited CYP2B1, and reduced TP metabolism.4. These results suggest that TP is a useful alternative model compound for investigating pharmacokinetics/pharmacodynamics and CYP-mediated drug-drug interactions.

Recently it has been suggested that the somas of the lacrimal nucleus and salivatory nuclei are, to a certain extent, anatomically intermingled all along the parvocellular reticular formation. The objective of this study was to investigate, using a physiological approach, the topographical relationship between salivatory and lacrimal cells. To this end the cell bodies of the superior (SSN) and inferior (ISN) salivatory nuclei were activated following a microinjection of NMDA. Results showed that NMDA administered to the SSN produced an increased secretion of submandibular-sublingual saliva, but not parotid saliva, concurrently with lacrimation. On the other hand, NMDA administered to the ISN produced hypersecretion of parotid, but not submandibular-sublingual saliva, concurrently with lacrimation. These secretory effects were blocked by i.p. administration of atropine but not when dihydroergotamine plus propranolol was administered, which points to the parasympathetic nature of the activated cells. Although the diffusion of the NMDA has not been evaluated directly, and it is not possible to pinpoint the anatomical specificity of the microinjections, these findings do suggest, from a functional perspective, the coexistence of salivatory and lacrimal cells in the same regions, or regions very close to one another, in the brainstem.

Cholinergic dysfunction is a key feature of cognitive impairment, and currently available acetylcholinesterase (AChE) inhibitors provide limited symptomatic benefit and are often associated with adverse effects. This study evaluated the cognitive-protective effects of bavachin (BVC), a prenylated flavonoid from Psoralea corylifolia, and its interaction with Donepezil (DNP) in a scopolamine (SCP)-induced amnesia model. Male Swiss albino mice were pretreated with BVC (10-40 mg/kg), DNP (2.5 mg/kg), or their combination for 7 days prior to SCP challenge, followed by assessment using multiple behavioral paradigms, including novel object recognition, elevated plus maze, passive avoidance, Y-maze, and Morris water maze. BVC attenuated SCP-induced memory deficits in a dose-dependent manner, with the 40 mg/kg dose producing performance statistically comparable to, though not formally demonstrated to be equivalent to, the normal control across tests. Bliss independence analysis of behavioral endpoints indicated predominantly additive interactions, with occasional greater-than-additive trends. Biochemical evaluation demonstrated that BVC inhibits AChE in vitro (IC50 = 27.7 µM) and attenuates SCP-induced elevations of AChE activity ex vivo in the frontal cortex and hippocampus. Combination treatment showed a greater-than-additive interaction in the frontal cortex (ΔBliss = 0.054) and an approximately additive effect in the hippocampus (ΔBliss = 0.013). Molecular docking and molecular dynamics simulations further suggested stable binding of BVC within the active sites of AChE and butyrylcholinesterase (BChE). Collectively, these findings indicate that BVC attenuates cognitive deficits, at least in part, through cholinesterase inhibition, and exhibits additive effects with DNP, supporting its potential as an adjunctive candidate for cognitive disorders.

This study aimed to evaluate the bioactivation of methyl-parathion (Me-Pa) and the expression and activity of mouse cytochrome P450 (Cyp) isoforms involved, in the cauda epididymis-vas deferens (CE-VD) and testis, and in the liver for comparison.Microsomes were obtained from adult mice treated and non-treated with phenobarbital (PB), and the bioactivation of Me-Pa was indirectly evaluated by in vitro acetylcholinesterase inhibition. The protein content was evaluated by immunoblotting, and the enzymatic activities by resorufin ether-O-dealkylation and 16α- and 6β-testosterone hydroxylation. Me-Pa bioactivation was observed in the testis at a lower rate than in the liver and was detected in the CE-VD only after PB induction.The protein content and enzymatic activities associated with the Cyps evaluated were observed in all tissues in different proportions, depending on the enzyme. In all cases, protein content and enzymatic activities in the liver were higher than in reproductive tissues, except for Cyp1a2, for which constitutive expression was not observed in the CE-VD, but its associated enzymatic activity was higher compared to the testis and liver.These findings suggest that mouse reproductive tissues are metabolically active in biotransforming xenobiotics, such as Me-Pa, contributing to its toxicity.