Fowler Joanna S, Logan Jean, Volkow Nora D, Shumay Elena, McCall-Perez Fred, Jayne Millard, Wang Gene-Jack, Alexoff David L, Apelskog-Torres Karen, Hubbard Barbara, Carter Pauline, King Payton, Fahn Stanley, Gilmor Michelle, Telang Frank, Shea Colleen, Xu Youwen, Muench Lisa
Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
New York University Langone Medical Center, Department of Radiology, New York, NY, USA.
Neuropsychopharmacology. 2015 Feb;40(3):650-7. doi: 10.1038/npp.2014.214. Epub 2014 Sep 24.
Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [(11)C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11-70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.
司来吉兰（L-司来吉兰）在常规剂量（口服10毫克/天）下是单胺氧化酶B（MAO-B）的选择性、不可逆抑制剂，用于治疗帕金森病。然而，对照研究表明，高剂量口服司来吉兰和透皮司来吉兰具有抗抑郁活性，这表明当司来吉兰的血浆水平升高时，脑MAO-A也可能受到抑制。速释型司来吉兰（Zelapar）是司来吉兰的口腔崩解制剂，与等量的传统司来吉兰相比，它通过颊黏膜吸收，产生更高的司来吉兰血浆水平，并减少苯丙胺代谢产物。尽管有间接证据表明高剂量的速释型司来吉兰对MAO-B失去了选择性，但没有直接证据表明它也能抑制人类大脑中的MAO-A。我们使用正电子发射断层扫描和MAO-A放射性示踪剂[(11)C]氯吉兰，在18名健康男性接受速释型司来吉兰（2.5、5.0或10毫克/天）治疗28天后，以及在3名接受司来吉兰透皮系统（Emsam贴片，6毫克/天）的受试者中测量了脑MAO-A。我们还在10毫克组的三名受试者中测量了多巴胺转运体（DAT）的可用性。10毫克速释型司来吉兰剂量显著抑制了MAO-A（36.9±19.7%，范围11-70%，p<0.007），但未抑制DAT；虽然Emsam也抑制了MAO-A（33.2±28.9（范围9-68%），但差异未达到显著性（p=0.10）），可能是因为样本量小。我们的结果提供了首个直接证据，证明司来吉兰制剂在人类中可抑制脑MAO-A，目前推测司来吉兰制剂除靶向MAO-B外还靶向脑MAO-A，但尚未得到证实。
