Metabolic correction of cerebral radiation syndrome.
DNA strand breaks that occur after irradiation activate the repair enzyme adenosine diphosphoribosyl transferase, which consumes NAD as a substrate and causes depletion first of neuronal NAD and then of the ATP pool. This is considered to be the crucial link in the mechanism underlying the cerebral radiation syndrome (CRS). In this study, two ways to correct the CRS metabolically were examined: (a) prevention of depletion of NAD after irradiation by administration of the enzyme inhibitor nicotinamide and (b) shunting the NAD-dependent oxidative phosphorylation pathway of ATP resynthesis by administration of a substrate of NAD-independent oxidation, succinate. Cerebral lesions induced by radiation were modeled by irradiation of rats or rat brain homogenates with 150 Gy of X rays. The manifestations of CRS in rats (excitement, convulsions, etc.) closely resembled those seen after acute hypoxia. In brain homogenates, pyruvate tetrazolium-reductase activity decreased after irradiation and could be corrected by addition of NAD after irradiation. Succinate tetrazolium-reductase activity was not affected by irradiation. Oxygen consumption by brain homogenates after irradiation in vitro and in situ decreased, as did oxygen consumption by rats in vivo after cranio-caudal irradiation. Administration of nicotinamide or succinate prevented both the postirradiation decrease in respiration (in both rats in vivo and brain homogenates in vitro) and the development of cerebral radiation syndrome. These results help to clarify the mechanisms underlying CRS and its metabolic correction.
Nosov
A V
AV
Military Medical Academy, ul. Lebedeva 6, St. Petersburg, 194044, Russia.
Ivnitsky
Y Y
YY
Malakhovsky
V N
VN
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D009536:Niacinamide / Q000627:therapeutic use; D010100:Oxygen / Q000378:metabolism; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000627:therapeutic use
D009536:Niacinamide; D019802:Succinic Acid; D010100:Oxygen