Based upon this outline of the steps involved in oxygen radical-induced oxidative damage, and LP in particular, a number of potential mechanisms for its inhibition are apparent which fall into three categories. The first category includes compounds that inhibit the initiation of LP and other forms of oxidative damage by preventing the formation of ROS or RNS species
. For instance, NOS inhibitors, discussed above exert an indirect antioxidant effect by limiting •NO production and thus PN formation. However, they also have the potential to interfere with the physiological roles that •NO is responsible for including antioxidant effects which are due it’s important role as a scavenger of lipid peroxyl radicals (e.g. AAOO• + •NO ➔ AAOONO
. Another approach to blocking posttraumatic radical formation is the inhibition of the enzymatic (e.g. cyclooxygenase, 5-lipoxygenases) AA cascade during which the formation of O2•-
is produced as a by-product of prostanoid and leukotriene synthesis. Kontos and colleagues 2, 25
and Hall and coworkers 26, 27
have shown that cyclooxygenase inhibiting non-steroidal anti-inflammatory agents (e.g. indomethacin, ibuprofen) are vaso-and neuro-protective in TBI models.
A second indirect LP inhibitory approach involves chemically scavenging the radical species
, •OH, •NO2
) before they have a chance to steal an electron from a polyunsaturated fatty acid and thus initiate LP. The use of pharmacologically-administered SOD represents an example of this strategy. Another example concerns the use of the nitroxide antioxidant tempol which has been shown to catalytically scavenge the PN-derived free radicals •NO2
and •CO3 28
. In either case, a general limitation to these first two approaches is that they would be expected to have a short therapeutic window and would have to be administered rapidly in order to have a chance to interfere with the initial posttraumatic “burst” of free radical production that has been documented in TBI models 2, 29
. While it is believed that ROS, including PN production persists several hrs after injury, the major portion is an early event that peaks in the first 60 minutes after injury making it clinically impractical to pharmacologically inhibit, unless the antioxidant compound is already “on board” when the injury occurs or available for administration immediately thereafter.
In contrast to the above indirect-acting antioxidant mechanisms, the third category involves stopping the “chain reaction” propagation of LP once it has begun. The most demonstrated way to accomplish this is by scavenging of lipid peroxyl (LOO•) or alkoxyl (LO•) radicals. The endogenous scavenger of these lipid radicals is alpha tocopherol or vitamin E (Vit E) which can donate an electron from its phenolic hydroxyl moiety to quench LOO●. However, the scavenging process is stoichiometric (1 Vit E can only quench 1 LOO•) and in the process vitamin E loses its antioxidant efficacy and becomes Vitamin E radical (LOO• + Vit E ➔ LOOH + Vit E•). Although Vit E• is relatively unreactive (i.e. harmless), it also cannot scavenge another LOO• until it is reduced back to its active form by receiving an electron from other endogenous antioxidant reducing agents such as ascorbic acid (Vitamin C) or glutathione (GSH). While this tripartite LOO• antioxidant defense system (Vit E, Vit C, GSH) works fairly effectively in the absence of a major oxidative stress, numerous studies have shown that each of these antioxidants is rapidly consumed during the early min. and hrs. after TBI. Thus, it has long been recognized that more effective pharmacological LOO• and LO• scavengers are needed. Furthermore, it is expected that compounds that could interrupt the LP process after it has begun would be able to exert a more practical neuroprotective effect (i.e. possess longer antioxidant therapeutic window).
A second approach to inhibiting the propagation of LP reactions is to chelate free iron, either ferrous (Fe++) or ferric (Fe+++), which potently catalyzes the breakdown of lipid hydroperoxides (LOOH), an essential event in the continuation of LP chain reactions in cellular membranes. The prototypical iron-chelating drug which chelates Fe+++, is the bacterially (streptomyces pilosus)-derived tri-hydroxamic acid compound deferoxamine.