title: Lactucopicrin potentiates neuritogenesis and neurotrophic effects by regulating Ca2+/CaMKII/ATF1 signaling pathway.
abstract: BACKGROUND
  Lactucopicrin is one of constitutes in Cichorium intybus L, which is commonly known as chicory in worldwide. It has been used for traditional usage such as antianalgesics, antidepressants and antihyperglycemics AIM OF STUDY: We investigated the neurotrophin-mediated neuroprotective effect of lactucopicrin in in vitro and examined for the underlying mechanism.
  
  
  METHODS
  To verify the neuroprotective effect of lactucopicrin, we investigated the inhibitory AChE activity, neurite outgrowth-related downstream signaling in murine neuroblastoma N2a and neurotrophins secretion in rat C6 glioma cells.
  
  
  RESULTS
  Lactucopicrin inhibited the AChE activity and increased intracellular Ca2+levels with a substantial rise in muscarinic acetylcholine receptor M1 (CHRM1) expression in N2a cells. Moreover, lactucopicrin actively promoted neurite outgrowth via Ca2+-mediated activation of Ca2+/calmodulin-dependent protein kinase-II (CaMKII). It further activates transcription factor 1 (ATF1) along with modulating the levels of tropomyosin receptor kinase A, extracellular signal-regulated kinase 1 and 2, AKT, and synaptophysin 1 in N2a cells. Additionally, the levels of neurotrophins including NGF, BDNF, and NT3 were increased by treatment of lactucopicrin in C6 cells. The effects of lactucopicrin on NGF secretion and neuritogenesis were maintained even in the presence of phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, indicating that lactucopicrin exerts its effect on neuritogenesis in a PI3K-independent manner.
  
  
  CONCLUSIONS
  Our results suggest that the natural compound lactucopicrin may be a promising neurotrophin-mediated neuroprotective candidate for neurodegenerative diseases.
authors.affiliation: College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea; Vanta Bioscience, K3, 11th Cross Street, SIPCOT Industrial Complex, Gummidipundi 601201, Tamil Nadu, India. Electronic address: vramamoorthysree@gmail.com.
authors.forename: Ramu
authors.initials: R
authors.lastname: Venkatesan
authors.affiliation: College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea. Electronic address: misterx95@gmail.com.
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
authors.affiliation: Department of Biochemistry, Gachon University College of Medicine, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea. Electronic address: euiju@gachon.ac.kr.
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Yeo
authors.affiliation: College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Medical Research Institute, Gil Medical Center, Inchon 21565, Republic of Korea; Gachon Institute of Pharmaceutical Science, Gachon University, #191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea. Electronic address: sunnykim@gachon.ac.kr.
authors.forename: Sun Yeou
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011506:Proteins / Q000502:physiology*; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D007783:Lactones; D018696:Neuroprotective Agents; D011506:Proteins; D012717:Sesquiterpenes; C001458:intybin; C079238:alcohol O-acetyltransferase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Acetylcholinesterase inhibitor; Ca(2+) influx; LY294002 (PubChem CID: 3973); Lactucopicrin; Lactucopicrin (PubChem CID: 174880); Neuritogenesis; Neurodegeneration; Neurotrophin; Retinoic acid (PubChem CID: 444795)