Tang Hui-Ling, Chen Si-Yu, Zhang Huan, Lu Ping, Sun Wei-Wen, Gao Mei-Mei, Zeng Xiang-Da, Su Tao, Long Yue-Sheng
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250 Changang East Road, Guangzhou, 510260, China.
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, 510260, China.
Cell Mol Neurobiol. 2022 Apr;42(3):777-790. doi: 10.1007/s10571-020-00974-4. Epub 2020 Oct 15.
Arachidonic acid (AA), a polyunsaturated fatty acid, is involved in the modulation of neuronal excitability in the brain. Arachidonate lipoxygenase 3 (ALOXE3), a critical enzyme in the AA metabolic pathway, catalyzes the derivate of AA into hepoxilins. However, the expression pattern of ALOXE3 and its role in the brain has not been described until now. Here we showed that the levels of Aloxe3 mRNA and protein kept increasing since birth and reached the highest level at postnatal day 30 in the mouse hippocampus and temporal cortex. Histomorphological analyses indicated that ALOXE3 was enriched in adult hippocampus, somatosensory cortex and striatum. The distribution was restricted to the neurites of function-specific subregions, such as mossy fibre connecting hilus and CA3 neurons, termini of Schaffer collateral projections, and the layers III and IV of somatosensory cortex. The spatiotemporal expression pattern of ALOXE3 suggests its potential role in the modulation of neural excitability and seizure susceptibility. In fact, decreased expression of ALOXE3 and elevated concentration of AA in the hippocampus was found after status epilepticus (SE) induced by pilocarpine. Local overexpression of ALOXE3 via adeno-associated virus gene transfer restored the elevated AA level induced by SE, alleviated seizure severities by increasing the latencies to myclonic switch, clonic convulsions and tonic hindlimb extensions, and decreased the mortality rate in the pilocarpine-induced SE model. These results suggest that the expression of ALOXE3 is a crucial regulator of AA metabolism in brain, and potentially acts as a regulator of neural excitability, thereby controlling brain development and seizure susceptibility.
花生四烯酸（AA）是一种多不饱和脂肪酸，参与调节大脑中的神经元兴奋性。花生四烯酸脂氧合酶3（ALOXE3）是AA代谢途径中的一种关键酶，催化AA转化为肝氧脂素。然而，迄今为止，ALOXE3在大脑中的表达模式及其作用尚未见报道。在此，我们发现小鼠海马体和颞叶皮质中，Aloxe3 mRNA和蛋白水平自出生后持续升高，并在出生后第30天达到最高水平。组织形态学分析表明，ALOXE3在成年海马体、体感皮层和纹状体中富集。其分布局限于功能特异性亚区域的神经突，如连接海马齿状回门区和CA3神经元的苔藓纤维、谢弗侧支投射的终末，以及体感皮层的III层和IV层。ALOXE3的时空表达模式表明其在调节神经兴奋性和癫痫易感性方面具有潜在作用。事实上，在匹鲁卡品诱导的癫痫持续状态（SE）后，海马体中ALOXE3表达降低，AA浓度升高。通过腺相关病毒基因转移局部过表达ALOXE3可恢复SE诱导的AA水平升高，通过增加肌阵挛转换、阵挛性惊厥和强直性后肢伸展的潜伏期来减轻癫痫严重程度，并降低匹鲁卡品诱导的SE模型中的死亡率。这些结果表明，ALOXE3的表达是大脑中AA代谢的关键调节因子，并可能作为神经兴奋性的调节因子，从而控制大脑发育和癫痫易感性。
