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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.

We hypothesized the general anesthetic thiopental effect depending on NO‐related mechanisms, consequently counteracted by stable gastric pentadecapeptide BPC 157. (i) To determine the general anesthetic effect of thiopental and possible counteraction depending on BPC 157 administration, all rats received intraperitoneally thiopental (20, 30, 40 mg/kg) while medication (BPC 157 (10 μg/kg, 10 ng/kg, 10 pg/kg) was given intraperitoneally at 5 min before thiopental. (ii) To determine NO‐related mechanisms, all rats received intraperitoneally thiopental 40 mg/kg while BPC 157 (10 μg/kg), L‐NAME (10 mg/kg), 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. (i) BPC 157 (10 ng/kg and 10 μg/kg), caused significant antagonism of general anesthesia produced by thiopental with a parallel shift of the dose‐response curve to the right. (ii) L‐NAME. Thiopental‐induced anesthesia duration was tripled. L‐arginine. Active only given with L‐NAME or BPC 157: habitual thiopental anesthesia time not influenced; potentiating effects of L‐NAME lessened, not abolished; shortening effect of BPC 157: abolished. BPC 157 and L‐NAME. Potentiating effects of L‐NAME was abolished. L‐NAME and L‐arginine and BPC 157. L‐NAME+L‐arginine+BPC 157 rats exhibited values close to those in BPC 157 rats. Thiopental general anaesthesia is simultaneously manipulated in both ways with NO‐system activity modulation, L‐NAME (prolongation) and BPC 157 (shortening/counteraction). BPC 157 and L‐arginine might serve two NO‐system pathways, more or less active, alternatively activated. Grant Funding Source: Supported by Grant 108‐ 1083570‐3635, Croatia

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