據(jù)美國(guó)每日科學(xué)網(wǎng)報(bào)道,，倫敦國(guó)王學(xué)院的彼得·吉斯領(lǐng)導(dǎo)的研究小組近日找到了影響精神分裂癥的分子途徑，并使用一種常用的抗癌藥物MS-275成功地緩解了小鼠的精神分裂癥癥狀,。這項(xiàng)研究為研發(fā)精神分裂藥物提供了新途徑,。論文發(fā)表在期刊《腦》（Brain）上。
精神分裂癥會(huì)導(dǎo)致幻覺(jué),、妄想和行為改變等長(zhǎng)期心理癥狀,，全球約2400萬(wàn)人受其影響，未經(jīng)治療的精神分裂患者有90%居于發(fā)展中國(guó)家,。雖然人們普遍認(rèn)為這是遺傳和環(huán)境的共同作用,，但其確切緣由尚未被知曉。目前精神分裂癥的治療方法,，包括心理治療如心理療法,、咨詢、認(rèn)知行為治療和藥物治療,，但很多抗精神病藥物和絕大多數(shù)的安定藥都有極大副作用,。
吉斯團(tuán)隊(duì)在研究中首次發(fā)現(xiàn)，精神分裂癥患者腦內(nèi)的酶催化劑p35變少,。正常的大腦發(fā)育部分是由Cdk5蛋白質(zhì)的活化作用所保證的,，而Cdk5的激活需要大腦中酶p35的存在，但精神分裂癥患者大腦中酶p35比正常人少50%,。
他們將小鼠的酶p35的含量減少到了相應(yīng)的比例,，然后對(duì)小鼠腦內(nèi)的分子變化進(jìn)行了監(jiān)控,。結(jié)果發(fā)現(xiàn)，p35的減少導(dǎo)致小鼠體內(nèi)對(duì)維持神經(jīng)連接有重要作用的突觸蛋白質(zhì)減少,，并顯露出神經(jīng)分裂相關(guān)癥狀,，如學(xué)習(xí)障礙、對(duì)感官刺激無(wú)法作出回應(yīng),，表現(xiàn)出認(rèn)知功能障礙等,。
研究還發(fā)現(xiàn)，p35的減少引起的分子變化與抗癌藥物MS-275的藥物靶點(diǎn)相一致,。MS-275不僅處理了小鼠的分子變化,，而且減少了其與精神分裂癥相關(guān)的癥狀。了解這一信號(hào)通路及p35減少所引起的后果,，對(duì)精神分裂癥潛在的治療方法有重要指導(dǎo)作用,。
吉斯稱，該研究成果鼓舞了未來(lái)治療精神分裂癥患者的藥物研發(fā),，有助于精神分裂癥的治療,。(生物谷 Bioon.com)
doi:10.1093/brain/awr155
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Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition
Olivia Engmann, Tibor Hortobágyi, Ruth Pidsley, Claire Troakes, Hans-Gert Bernstein, Michael R. Kreutz, Jonathan Mill, Margareta Nikolic and Karl Peter Giese
Cyclin-dependent kinase 5 is activated by small subunits, of which p35 is the most abundant. The functions of cyclin-dependent kinase 5 signalling in cognition and cognitive disorders remains unclear. Here, we show that in schizophrenia, a disorder associated with impaired cognition, p35 expression is reduced in relevant brain regions. Additionally, the expression of septin 7 and OPA1, proteins downstream of truncated p35, is decreased in schizophrenia. Mimicking a reduction of p35 in heterozygous knockout mice is associated with cognitive endophenotypes. Furthermore, a reduction of p35 in mice results in protein changes similar to schizophrenia post-mortem brain. Hence, heterozygous p35 knockout mice model both cognitive endophenotypes and molecular changes reminiscent of schizophrenia. These changes correlate with reduced acetylation of the histone deacetylase 1 target site H3K18 in mice. This site has previously been shown to be affected by truncated p35. By restoring H3K18 acetylation with the clinically used specific histone deacetylase 1 inhibitor MS-275 both cognitive and molecular endophenotypes of schizophrenia can be rescued in p35 heterozygous knockout mice. In summary, we suggest that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1.
