Free radical induced oxidative damage to DNA: relation to brain aging and neurological disorders.

Free radicals are produced in cells by cellular metabolism and by exogenous agents. These species react with biomolecules in cells and one of the important targets is DNA. This kind of damage, often referred to as oxidative DNA damage, has consequences in various organs and particularly in brain, in view of its high metabolic activity and oxygen consumption. The consequences include mutagenesis of various kinds ranging from simple oxidation of bases to large deletions through single and double strand breaks. In brain, because of its post-mitotic nature, oxidative damage to DNA is seen more often at the level of bases. A major route for repairing oxidative damage to bases is base excision repair (BER). It is increasingly becoming apparent that defects in repairing oxidative DNA damage can lead to a number of neurological disorders like Alzheimer and Parkinson. Our recent studies have clearly demonstrated that BER is highly compromised in brain cells with increasing age and this could well be one of the major causative factors for normal aging and the associated deteriorating mental conditions, including certain neurological abnormalities.

Effect of hydroxyurea on subcellular activities of thymidine kinase in developing and aging rat brain.

Hydroxyurea, when injected intraperitoneally at a dose of 1 mg/g body weight, inhibited thymidine kinase activity in developing rat cerebrum (16-day-embryonic) and cerebellum (7-day-postnatal) within a few hours of administration. The inhibition was timedependent and both cytosolic and mitochondrial thymidine kinases were affected. Under the same conditions, the activities of certain other enzymes concerned with DNA metabolism, viz., DNA polymerase, and acid and alkaline DNases were not inhibited. Further, the addition of hydroxyurea in vitro had no effect on the activity of any of the enzymes studied. However, similar treatment given to 2-year-old rat failed to exert any inhibition on either the mitochondrial or soluble thymidine kinase activities in grey and white matter regions of cerebrum and cerebellum. It is inferred that hydroxyurea, apart from its already known effect on ribonucleotide reductase of replicating cells, also affects thymidine kinase.

Inhibition of thymidine kinase activity by hydroxyurea during highly and less proliferative regions of rat brain.

Hydroxyurea, when injected intraperitoneally, exerted marked inhibition on the activity of thymidine kinase in 5 day old postnatal cerebellum and 15 day old embryonic cerebrum. However, it failed to show any sustained inhibition on thymidine kinase activity in 5 day old postnatal cerebrum. In this case, the marginal decrease of thymidine kinase activity noticed during early intervals reversed back to more than normal value at a later time interval. These results along with our earlier findings are taken to indicate the differential action of this drug on thymidine kinase activity in rapidly and slowly proliferating regions of rat brain.

DNA, RNA, protein and DNases in developing rat cerebellum: Effects of early postnatal nutritional deprivation.

The effect of early postnatal undernutrition and subsequent rehabilitation on wet weight, DNA, RNA, protein and the activities of acid and alkaline DNases in the cerebellar region of rat brain was studied. The cerebellar region was found to be affected significantly during early undernutrition. Further, earlier the initiation of nutritional rehabilitation the better was the recovery and in some cases timely nutritional rehabilitation resulted in better than normal biochemical composition of the brain. The specific activities of acid and alkaline DNases were not affected by early undernutrition. However, the total activities of these enzymes were significantly low in undernourished rats (R15 and R21) Rehabilitation of these deprived groups upto 150 days resulted in higher amounts of these enzymes as compared to those of age-matched controls. It is concluded that the two DNases, are synthesized in a preferential manner during rehabilitation, It is further concluded that cerebellar region, in terms of development schedule and response to imposed calorie restriction, is intermediary between grey and white matter regions.