A molecular basis for the efficacy of magnesium treatment following traumatic brain injury in rats.
Magnesium ions have been shown to be a promising treatment for brain lesions caused by traumatic brain injury (TBI), as well as for the associated acute neurodegeneration and progressive functional deficits. This study investigated the effects of magnesium on the expression of the cell death/survival related proteins following TBI. Male Sprague-Dawley (SD) rats (n = 66, 280-320 g body weight) were subjected to sham surgery alone (n = 14), or to the surgery followed by a lateral fluid percussion brain injury of moderate severity (n = 52, 2.4-2.7 atm). The injured rats were randomly treated with an intravenous bolus of magnesium chloride (n = 26, 125 micromol) or saline vehicle (n = 26). The coronal brain sections were quantitatively analyzed for cell apoptosis and the expression of p53-related proteins, Bcl-2, cyclin D1 and PCNA at 1, 2, and 4 days post-injury by immunohistochemistry or in situ hybridization. Tissue damage was observed primarily in the ipsilateral cortex of the injured region with the induction of apoptosis and p53 mRNA level at 2 days after TBI. The expression of p53 and responding proteins (p21(WAF1/CIP1), Mdm2 and Bax) showed a temporal pattern similar to the apoptotic events in the time course experiments. They were induced in the early time points of days 1-2, decreasing by day 4 after TBI. In contrast, the expression of the cell survival related proteins - Bcl-2, cyclin D1, and PCNA - was most significant at day 4 post-injury, when the rate of apoptosis decreased. Magnesium treatment resulted in a reduction in apoptosis and expression of p53-related proteins. However, it had only a slight additive effect on the expression of the survival related proteins in the same time-course. These results provide a molecular basis for the efficiency of magnesium in treating TBI-induced tissue damage.
Lee
Jin Suk
JS
Department of Rehabilitation Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea.
Han
Young Min
YM
Yoo
Do Sung
DS
Choi
Seung Jin
SJ
Choi
Byung Hyune
BH
Kim
Jong Hyun
JH
Kim
Young Hoon
YH
Huh
Pil Woo
PW
Ko
Young Jin
YJ
Rha
Hyoung Kyun
HK
Cho
Kyung Suck
KS
Kim
Dal Soo
DS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D015636:Magnesium Chloride / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects
D018696:Neuroprotective Agents; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D015636:Magnesium Chloride; D019938:Cyclin D1