Lysophosphatidic acid induces thrombospondin‐1 production in primary cultured rat cortical astrocytes

Lysophosphatidic acid (LPA), a brain membrane‐derived lipid mediator, plays important roles including neural development, function, and behavior. In the present study, the effects of LPA on astrocyte‐derived synaptogenesis factor thrombospondins (TSPs) production were examined by real‐time PCR and western blotting, and the mechanism underlying this event was examined by pharmacological approaches in primary cultured rat cortical astrocytes. Treatment of astrocytes with LPA increased TSP‐1 mRNA, and TSP‐2 mRNA, but not TSP‐4 mRNA expression. TSP‐1 protein expression and release were also increased by LPA. LPA‐induced TSP‐1 production were inhibited by AM966 a LPA1 receptor antagonist, and Ki16425, LPA1/3 receptors antagonist, but not by H2L5146303, LPA2 receptor antagonist. Pertussis toxin, Gi/o inhibitor, but not YM‐254890, Gq inhibitor, and NF499, Gs inhibitor, inhibited LPA‐induced TSP‐1 production, indicating that LPA increases TSP‐1 production through Gi/o‐coupled LPA1 and LPA3 receptors. LPA treatment increased phosphorylation of extracellular signal‐regulated kinase (ERK), p38 mitogen‐activated protein kinase (MAPK), and c‐Jun N‐terminal kinase (JNK). LPA‐induced TSP‐1 mRNA expression was inhibited by U0126, MAPK/ERK kinase (MEK) inhibitor, but not SB202190, p38 MAPK inhibitor, or SP600125, JNK inhibitor. However, LPA‐induced TSP‐1 protein expression was diminished with inhibition of all three MAPKs, indicating that these signaling molecules are involved in TSP‐1 protein production. Treatment with antidepressants, which bind to astrocytic LPA1 receptors, increased TSP‐1 mRNA and protein production. The current findings show that LPA/LPA1/3 receptors signaling increases TSP‐1 production in astrocytes, which could be important in the pathogenesis of affective disorders and could potentially be a target for the treatment of affective disorders. The following cascade for Lysophosphatidic acid (LPA)‐mediated astrocyte‐derived synaptogenesis factor thrombospondin‐1 (TSP‐1) production in rat primary cultured cortical astrocytes were proposed. Activation of Gi/o‐coupled LPA1 and LPA3 receptors evoke ERK, p38 MAPK, and JNK activation, and then TSP‐1 mRNA protein are induced. Several different classes of antidepressants, which bind to astrocytic LPA1 receptors, significantly increased TSP‐1 mRNA and protein production. These finding should provide implications for the understanding of the pathophysiology of neurological disorders, including affective disorders