Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage.
Herein, we show that a single injection of P4 (4 mg/kg) at 1 h or 48 h, but not 96 h, before middle cerebral artery occlusion (MCAO) produces significant protective effects against the ischemia-induced neuronal death and the deficits in spatial cognition and LTP induction. The present study focused on the molecular mechanisms underlying the neuroprotection exerted by P4 administration at 1 h and 48 h pre-MCAO, termed acute and delayed P4-neuroprotection, respectively. Pharmacology suggested that P4-receptor (P4R) cascading to a Src-ERK1/2 signaling mediated the delayed P4-neuroprotection. To support this, it was observed by anti-phosph-ERK1/2 immunoblots that a single injection of P4 triggered a P4R-mediated persistent increase in ERK1/2 phosphorylation and their nuclear translocation for 48 h. In contrast, the acute P4-neuroprotection did not depend on the P4R-mediated Src-ERK1/2 signaling. Instead, the acute P4-administration attenuated the NMDA-induced rise in the intracellular calcium concentration ([Ca(2+)](i)) that may be a primary cause for MCAO-induced neuronal injury. This effect seemed to be exerted by an antagonism of sigma(1) receptor since the sigma(1) receptor antagonist NE100 perfectly mimicked the acute P4-neuroprotection and also attenuated the NMDA-induced [Ca(2+)](i) increase. These findings suggest that the P4 neuroprotection involves two independent processes depending on the timing of P4 administration before MCAO: an acute protection by antagonizing sigma(1) receptor to inhibit NMDAr-Ca(2+) influx and a delayed one by an activation of P4R-mediated Src-ERK signaling pathway.
Laboratory of Reproductive Medicine, Nanjing Medical University, Hanzhong Road 140, Jiangsu, China.
Weiyan
W
Cai
Ying
Y
Zhu
Kishio
K
Furuya
Zhen
Z
Li
Masahiro
M
Sokabe
Ling
L
Chen
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D006727:Hormone Antagonists / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D015735:Mifepristone / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D016900:Neurofilament Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011374:Progesterone / Q000008:administration & dosage*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors
D006727:Hormone Antagonists; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; C044882:neurofilament protein L; D015735:Mifepristone; D011374:Progesterone; D016202:N-Methylaspartate; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium