Prevention of Mitochondrial Dysfunction

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Mitochondrial dysfunction has been increasingly recognized as a key player in the postischemic and posttraumatic secondary injury.59'60 It is clear that this is directly related to Ca2 + ions, which alter mitochondrial function and increase ROS production. For example, loss of mitochondrial homeostasis, increased mitochondrial ROS production, and disruption of synaptic homeostasis occur after TBI, implicating a pivotal role for mitochondrial dysfunction in the neuropathological sequalae that follow the mechanical trauma. This theory has been solidified by the demonstration that therapeutic intervention with the immunosuppressant, cyclosporine A (CsA) following experimental TBI reduces mitochondrial dysfunction and cortical damage, as well as cytoskeletal changes and axonal dysfunction.61-63 These neuroprotective effects of CsA result from the ability of the drug to bind to cyclophilin D, thus preventing binding of the latter to the adenine nucleotide translocator protein (ANT), blocking the interaction of ANT with the mitochondrial permeability transition (MPT) pore. In the absence of cyclophilin D/ANT binding to the MPT pore, the MPT pore cannot open and MPT cannot occur; the mitochondrion is protected from a catastrophic loss of its membrane potential (DC) and metabolic failure and the neuronal energy metabolism (ATP generation) is preserved. Cyclosporine A is currently in phase II clinical trials in TBI. However, its neuroprotective efficacy, based on its mitochondrial protective mechanism, is potentially compromised by its immunosuppressive properties and the well-known ability to elicit renal and/or CNS toxicity, effects related to the ability of CsA to bind calcineurin. To circumvent these properties, the N-methylleucine residue in position 3 of CsA has been converted in the recently described new compound entity (NIM811) to an N-methylisoleucine, which eliminates calcineurin binding and its associated immunosuppressive and toxic properties.64 Recent studies have demonstrated that NIM811 can replicate the ability of CsA to protect brain and spinal cord mitochondrial function in TBI and SCI models, respectively.65

Evidence has begun to accumulate that the particular ROS formed by mitochondria is peroxynitrite. NO is present in mitochondria, and a mitochondrial NOS isoform (mtNOS) has been isolated, Although probably playing a key physiological role in mitochondria, dysregulation of mitochondrial "NO generation and the aberrant production of the toxic metabolite peroxynitrite appear to play a role in many, if not all, the major acute and chronic neurodegenerative conditions.66 Exposure of mitochondria to Ca2 +, which renders them dysfunctional, results in peroxynitrite generation, which in turn triggers mitochondrial Ca2 + release (i.e., limits their Ca2 + uptake or buffering capacity).67 Both peroxynitrite forms, ONOO- and ONOOCO2, deplete mitochondrial antioxidant stores and cause protein nitration. The relatively long half-life of peroxynitrite in comparison to other short-lived ROS also allows for mtNOS-derived peroxynitrite to diffuse between cells.

Figure 8 illustrates the formation of peroxynitrite in mitochondria during ischemic or traumatic insults. As shown, O-2 radical production is a byproduct of the mitochondrial electron transport chain during ATP generation. Electrons escape from the chain and reduce O2 to O2. Normally, cells convert O2 to H2O2, utilizing manganese superoxide dismutase (MnSOD), which is also localized to the mitochondria. However, if pathophysiological insults (e.g., mechanical trauma) trigger an increase in intracellular Ca2 +, causing an increase in mtNOS activity and "NO

Intermembrane space

Intermembrane space

Figure 8 Schematic diagram of the mitochondrial electron-transport chain, showing the site of formation of superoxide (O2) and nitric oxide ('NO). These two radicals interact to form peroxynitrite anion (ONOO-). The rate constant for this reaction is reported to be 1.6 x 1010M -1 s-1, as reported by Nauser and Koppenol.68 This is faster than the frequently reported rate constant for the dismutation of superoxide by the mitochondrial manganese superoxide dismutase (MnSOD), which is only 1.4 x 109M-1 sc-1. Thus the formation of peroxynitrite is favored.

Figure 8 Schematic diagram of the mitochondrial electron-transport chain, showing the site of formation of superoxide (O2) and nitric oxide ('NO). These two radicals interact to form peroxynitrite anion (ONOO-). The rate constant for this reaction is reported to be 1.6 x 1010M -1 s-1, as reported by Nauser and Koppenol.68 This is faster than the frequently reported rate constant for the dismutation of superoxide by the mitochondrial manganese superoxide dismutase (MnSOD), which is only 1.4 x 109M-1 sc-1. Thus the formation of peroxynitrite is favored.

Figure 9 Schematic diagram of the sequence of events occurring in posttraumatic or postischemic mitochondrial damage and possible intervention points for neuroprotective therapy.

liberation, peroxynitrite formation is a certainty, since the rate constant for the reaction of "NO with O- greatly exceeds the rate constant for dismutation of O- by MnSOD.68 Peroxynitrite then damages mitochondria by tyrosine nitration and by causing LP and the production of 4-HNE that conjugates to mitochondrial membrane proteins, impairing their function. An efficient scavenger of peroxynitrite, or its derived radical species, would be expected to protect mitochondrial function from oxidative damage.

Another approach to mitochondrial protection involves the use of pharmacological 'uncoupling' agents that facilitate the proton movement from the mitochondrial inner membrane space into the mitochondrial matrix. This results in the pumping of protons out of the matrix via the electron-transport system, being 'uncoupled' from proton flow into the matrix during the operation of the ATP synthase. Consequently, the membrane potential DC is reduced, which in turn decreases mitochondrial calcium uptake and ROS production, which are linked to DC. In support of this strategy, the well-known mitochondrial uncoupler 2,4-dinitrophenol protects mitochondrial function and exerts a neuroprotective effect in rodent models of stroke, TBI, and SCI.60 However, the goal of this approach is to achieve a modest level of uncoupling and only slightly decreasing DC from a normal level of 160 mV down to 140 mV Any greater decrease in membrane potential would decrease ATP synthesis and lead to mitochondrial failure. The currently available uncouplers, such as 2,4-DNP, although sufficient for proof of concept, have a sharp, U-shaped neuroprotective dose-response curve due to their ability to move readily from the desired 'modest uncoupling' mode to a level of severe uncoupling (decrease in DC to within the range 140-100 mV or lower). Whether it is possible to discover safer uncoupling compounds that will only be capable of decreasing DC down to a neuroprotective level, and not beyond, remains to be demonstrated. The search, however, appears worthwhile, since the magnitude of mild uncoupling-induced neuroprotection in rodent CNS injury models is truly impressive, and this mechanistic strategy is equally applicable to stroke, TBI, and SCI. Figure 9 summarizes the different steps involved in postischemic or posttraumatic mitochondrial failure and possible points of pharmacological intervention.

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