ABSTRACT
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
In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 µg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.
