The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

中文翻译：

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天然原生物碱甲基-2-氨基-3-甲氧基苯甲酸酯 (MAM) 可减轻大鼠和小鼠精神分裂症模型的阳性症状和认知症状


开发具有促认知特性和较少副作用的新型抗精神病药物是精神分裂症药物研究的重点。在这项研究中，我们首次对有前景的天然非典型抗精神病药物 Mmethyl-2-Amino-3-MethoxyBenzate (MAM) 的作用进行了临床前探索，MAM 是一种来自植物 Nigella damascena 种子的可渗透大脑的原生物碱。使用与高多巴胺能活性相关的动物模型，即药物遗传学阿朴吗啡（D2/D1 受体激动剂）敏感（APO-SUS）大鼠模型和药理学诱导的小鼠和大鼠精神分裂症模型，我们发现 MAM 减少了由阿朴吗啡（D2/D1 受体激动剂）诱导的啃咬刻板行为和攀爬行为多巴胺能药物。这预示着抗精神病活性。与此一致，MAM 拮抗 APO-SUS 大鼠死后大脑伏隔核和背外侧纹状体中阿朴吗啡诱导的 c-Fos 和 NPAS4 mRNA 水平。此外，苯环己哌啶（PCP，一种 NMDA 受体拮抗剂）和 2,5-二甲氧基-4-碘安非他明（DOI，一种 5HT2A/2C 受体激动剂）诱导前脉冲抑制缺陷，反映了精神分裂症的阳性症状，这些症状通过 MAM 治疗得以挽救和非典型抗精神病药类似。死后大脑免疫染色显示，MAM 阻断了许多皮质区域中 PCP 和 DOI 诱导的 c-Fos 免疫反应的强烈激活。最后，在 28 天的亚慢性治疗方案中，MAM 不会引起体重增加、高血糖、高脂血症或肝肾毒性作用，以及已知由非典型抗精神病药引起的副作用。 MAM 也没有表现出任何强直效应。 总之，MAM 的大脑渗透性、明显不存在临床前副作用以及拮抗与精神分裂症相关的阳性和认知症状的能力，使 MAM 成为一种令人兴奋的新型抗精神病药物，值得临床测试。