Halim Nader D, Lipska Barbara K, Hyde Thomas M, Deep-Soboslay Amy, Saylor E Michael, Herman Mary M, Thakar Jay, Verma Ajay, Kleinman Joel E
Graduate Program in Molecular and Cell Biology, Bethesda, MD 20814, USA.
J Neurosci Methods. 2008 Mar 30;169(1):208-13. doi: 10.1016/j.jneumeth.2007.11.017. Epub 2007 Nov 29.
A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia (n=35) are increased relative to control subjects (n=42) by 28%, p=0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH, and that this correlation is particularly strong in patients (r=-0.78, p=3E-6). Third, we have shown in rats that chronic haloperidol (0.8mg/kg/day) and clozapine (5mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p<0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia.
多项尸检研究发现，精神分裂症患者大脑中的pH值降低。鉴于较低的pH值与死后人类大脑中mRNA表达降低有关，精神分裂症患者大脑中pH值降低可能是患者与对照组比较中的一个重要潜在混杂因素。我们假设pH值降低可能与乳酸浓度升高有关。然而，与之前认为乳酸增加代表精神分裂症原发性代谢异常的证据这一观点相反，我们假设这种增加是先前抗精神病药物治疗的继发结果。我们通过以下方式对此进行了验证：首先证明，与对照组（n = 42）相比，精神分裂症患者（n = 35）小脑的乳酸水平升高了28%，p = 0.001。其次，我们表明小脑乳酸水平与pH值之间存在极佳的相关性，且这种相关性在患者中尤为强烈（r = -0.78，p = 3×10⁻⁶）。第三，我们在大鼠中发现，相对于赋形剂，慢性给予氟哌啶醇（0.8mg/kg/天）和氯氮平（5mg/kg/天）可使额叶皮质中的乳酸浓度增加（分别增加31%和22%，p < 0.01）。这些数据表明，精神分裂症患者死后大脑中乳酸增加与pH值降低有关，且这些变化可能与抗精神病药物治疗有关，而非精神分裂症患者前额叶皮质的原发性代谢异常。
