Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.
Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.
Behav Brain Res. 2021 Jan 1;396:112919. doi: 10.1016/j.bbr.2020.112919. Epub 2020 Sep 18.
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.
在适合的大鼠模型中，我们专注于稳定的十五肽 BPC 157、L-NAME、NOS 抑制剂和 L-精氨酸、NOS 底物，研究它们对精神分裂样症状的影响。药物（腹膜内注射 mg/kg）为 L-NAME（5）、L-精氨酸（100）、BPC 157（0.01），单独或联合使用，在急性扰乱运动活动的挑战前 5 分钟给予（多巴胺间接/直接激动剂（安非他命（3.0），阿扑吗啡（2.5）），NMDA 受体非竞争性拮抗剂（MK-801（0.2））或僵住，（多巴胺受体拮抗剂氟哌啶醇（2.0））。或者，在腹膜内注射 L-NAME 40mg/kg 后立即给予 BPC 157 10μg/kg。为了诱导或预防敏化，我们使用慢性甲基苯丙胺给药，在头 3 周的第 3 天交替进行，在下一个 4 周后进行挑战，并在第 2 周和第 3 周的甲基苯丙胺前 5 分钟描述药物（L-NAME、L-精氨酸、BPC 157）。单独给予时，BPC 157 或 L-精氨酸可对抗安非他命、阿扑吗啡和 MK-801 诱导的作用、氟哌啶醇诱导的僵住和慢性甲基苯丙胺诱导的敏化。L-NAME 不影响阿扑吗啡和 MK-801 诱导的作用、氟哌啶醇诱导的僵住和慢性甲基苯丙胺诱导的敏化，但可对抗急性安非他命诱导的作用。在组合（L-NAME+L-精氨酸）中，作为 NO 特异性拮抗作用，L-NAME 拮抗 L-精氨酸在阿扑吗啡、MK-801、氟哌啶醇和甲基苯丙胺大鼠中的拮抗作用，但在安非他命大鼠中没有拮抗作用。与 L-精氨酸不同，BPC 157 在 NOS 阻断（L-NAME+BPC 157）或 NO 系统过度刺激（L-精氨酸+BPC 157）存在的情况下保持其拮抗作用。说明 BPC 157 和 L-精氨酸之间的关系，BPC 157 恢复了拮抗作用（L-NAME+L-精氨酸+BPC 157），当 L-NAME 与 L-精氨酸联合给药时，拮抗作用被取消（L-NAME+L-精氨酸）。最后，BPC 157 直接抑制 L-NAME 高剂量诱导的僵住。进一步的研究将确定 BPC 157/多巴胺/谷氨酸/NO 系统的确切关系和临床应用。
