Polyunsaturated fatty acids (PUFAs) can induce neurogenesis and recovery from brain diseases. However, the exact mechanisms of the beneficial effects of PUFAs have not been conclusively described. We recently reported that docosahexaenoic acid (DHA) induced neuronal differentiation by decreasing Hes1 expression and increasing expression, which causes cell cycle arrest in neural stem cells (NSCs). In the present study, we examined the effect of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on differentiation, expression of basic helix-loop-helix transcription factors (Hes1, Hes6, and NeuroD), and the cell cycle of cultured NSCs. EPA also increased mRNA levels of Hes1, an inhibitor of neuronal differentiation, Hes6, an inhibitor of Hes1, NeuroD, and Map2 mRNA and Tuj-1-positive cells (a neuronal marker), indicating that EPA induced neuronal differentiation. EPA increased the mRNA levels of and , a cyclin-dependent kinase inhibitor, which indicated that EPA induced cell cycle arrest. Treatment with AA decreased Hes1 mRNA but did not affect NeuroD and Map2 mRNA levels. Furthermore, AA did not affect the number of Tuj-1-positive cells or cell cycle progression. These results indicated that EPA could be involved in neuronal differentiation by mechanisms alternative to those of DHA, whereas AA did not affect neuronal differentiation in NSCs. 1. Introduction Polyunsaturated fatty acids (PUFAs) are critical for the developing brain and are classified into omega-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFAs, such as arachidonic acid (AA). Only low levels of many PUFAs are synthesized from their respective shorter-chain precursors in mammals; thus, they need to be obtained from dietary sources. Dysregulation of fatty acid and phospholipid metabolism can induce a wide range of psychiatric, neurological, and developmental disorders in adults [1]. The enhancement of neurogenesis is an important tool to treat brain disorders and has been shown to ameliorate or prevent mental illnesses [2], cholinergic denervation [3], and neurodegenerative diseases [4]. Omega-3 PUFAs reportedly enhanced neurogenesis in adult rat hippocampi [5], brain tissue of lobsters [6], and in fat-1 transgenic mice [7]. Bertrand et al. [8] show that cortical development is disrupted by feeding omega-3 deficient diets in embryonic rats. AA has also been shown to enhance neurogenesis in rat hippocampi [9], and AA enhance proliferation and astrogenesis of fetal rat neuronal stem/progenitor cells (NSCs) [10]. However, the exact mechanisms of the
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