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We attempted throughout the NO-system to achieve the particular counteraction of the ketamine-induced resembling "negative-like" schizophrenia symptoms in rats using pentadecapeptide BPC 157, and NO-agents, NG-nitro-L-arginine methylester (L-NAME), and/or L-arginine, triple application. This might be the find out the NO-system organized therapy (i.e., simultaneously implied NO-system blockade (L-NAME) vs. NO-system over-stimulation (L-arginine) vs. NO-system immobilization (L-NAME+L-arginine)). The ketamine regimen (intraperitoneally/kg) included: 3 mg (cognitive dysfunction, novel object recognition test), 30 mg (anxiogenic effect (open field test) and anhedonia (sucrose test)), and 8 mg/3 days (social withdrawal). Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), and BPC 157 (0.01), alone and/or together, given immediately before ketamine (L-NAME, L-arginine, and combination) or given immediately after (BPC 157 and combinations). BPC 157 counteracted ketamine-cognition dysfunction, social withdrawal, and anhedonia, and exerted additional anxiolytic effect. L-NAME (antagonization, social withdrawal) and L-arginine (antagonization, cognitive dysfunction, anhedonia) both included worsening cognitive dysfunction, anhedonia, and anxiogenic effect (L-NAME), social withdrawal, and anxiogenic effect (L-arginine). Thus, ketamine-induced resembling "negative-like" schizophrenia symptoms were "L-NAME non-responsive, L-arginine responsive" (cognition dysfunction), "L-NAME responsive, L-arginine non-responsive" (social withdrawal), "L-NAME responsive, L-arginine responsive, opposite effect" (anhedonia) and "L-NAME responsive, L-arginine responsive, parallel effect" (both anxiogening). In cognition dysfunction, BPC 157 overwhelmed NO-agents effects. The mRNA expression studies in brain tissue evidenced considerable overlapping of gene overexpression in healthy rats treated with ketamine or BPC 157. With the BPC 157 therapy applied immediately after ketamine, the effect on Nos1, Nos2, Plcg1, Prkcg, and Ptgs2 (increased or decreased expression), appeared as a timely specific BPC 157 effect on ketamine-specific targets. [ABSTRACT FROM AUTHOR]

Aim: We hypothesized that certain effects of the general anaesthetic thiopental are dependent on NO-related mechanisms, which were consequently counteracted by stable gastric pentadecapeptide BPC 157. Main methods: (1) All rats intraperitoneally received thiopental (20, 30, 40, and 50 mg/kg) while medication BPC 157 (10 μg/kg, 10 ng/kg, and 10 pg/kg) was given intraperitoneally at 5 min before thiopental. (2) To determine NO-related mechanisms, all rats received intraperitoneally thiopental 40 mg/kg while BPC 157 (10 μg/kg), l-NAME (10 mg/kg) and l-arginine (30 mg/kg) were applied alone and/or combined. BPC 157 was given at 25 min before thiopental while l-NAME, l-arginine, alone and/or combined, were applied at 20 min before thiopental. Key findings: (1) BPC 157 own effect on thiopental anaesthesia: BPC 157 (10 ng/kg and 10 μg/kg) caused a significant antagonism of general anaesthesia produced by thiopental with a parallel shift of the dose-response curve to the right. (2) l-NAME- l-arginine-BPC 157 interrelations: l -NAME: Thiopental-induced anaesthesia duration was tripled. l- arginine: Usual thiopental anaesthesia time was not influenced. Active only when given with l-NAME or BPC 157: potentiating effects of l-NAME were lessened, not abolished; shortening effect of BPC 157: abolished. BPC 157 and l -NAME: Potentiating effects of l-NAME were abolished. BPC 157 and l -NAME and l- arginine: BPC 157 + l-NAME + l-arginine rats exhibited values close to those in BPC 157 rats. Significance: Thiopental general anaesthesia is simultaneously manipulated in both ways with NO system activity modulation, l-NAME (prolongation) and BPC 157 (shortening/counteraction) and l-arginine (interference with l-NAME and BPC 157). [ABSTRACT FROM AUTHOR]