Late Administration of a Palladium Lipoic Acid Complex (POLY-MVA) Modifies Cardiac Mitochondria but Not Functional or Structural Manifestations of Radiation-Induced Heart Disease in a Rat Model.

Exposure of the heart to ionizing radiation can cause adverse myocardial remodeling. In small animal models, local heart irradiation causes persistent alterations in cardiac mitochondrial function and swelling. POLY-MVA is a dietary supplement that contains a palladium lipoic acid complex that targets mitochondrial complex I and has been demonstrated to have greater redox potential than lipoic acid alone. POLY-MVA improves mitochondrial function and anti-oxidant enzyme activity in the aged rat heart. In this study, we tested whether POLY-MVA can mitigate cardiac effects of ionizing radiation. Adult male rats were exposed to local heart X rays with a daily dose of 9 Gy for 5 consecutive days. Eighteen weeks after irradiation, POLY-MVA was administered orally at 1 ml/kg bodyweight per day during weekdays, for 6 weeks. Alterations in cardiac function as measured with echocardiography coincided with enhanced mitochondrial swelling, a reduction in mitochondrial expression of complex II, manifestations of adverse remodeling such as a reduction in myocardial microvessel density and an increase in collagen deposition and mast cell numbers. POLY-MVA enhanced left ventricular expression of superoxide dismutase 2, but only in sham-irradiated animals. In irradiated animals, POLY-MVA caused a reduction in markers of inflammatory infiltration, CD2 and CD68. Moreover, POLY-MVA mitigated the effects of radiation on mitochondria. Nonetheless, POLY-MVA did not mitigate adverse cardiac remodeling, suggesting that this tissue remodeling may not be alleviated by altering cardiac mitochondria alone. However, we cannot exclude the possibility that an earlier onset of POLY-MVA administration may have more profound effects on radiation-induced cardiac remodeling.

Vasoactive intestinal peptide attenuates cytochrome c translocation, and apoptosis, in rat hippocampal stem cells.

While widely distributed in the brain, one area with concentrated levels of vasoactive intestinal peptide (VIP) is the hippocampus. In this study, rat hippocampal stem cells were used to examine VIP's effects on apoptotic cell death induced by withdrawal of trophic support. In the apoptotic cascade, the translocation of cytochrome c from the mitochondria to the cytoplasm activates caspases, resulting in cell death. VIP decreased this translocation of cytochrome c in a dose-dependent manner, and reduced apoptosis. This demonstrates that VIP regulates neuronal apoptosis and may contribute to stem cell homeostasis.

Modulation of apoptotic regulatory proteins and early activation of cytochrome C following systemic 3-nitropropionic acid administration.

The present study utilized the administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), to mimic the pathology associated with Huntington's disease (HD). 3-NP causes striatal cell degeneration via the inhibition of succinate dehydrogenase. There is growing evidence suggesting the role of apoptosis in 3-NP cell death. TUNEL staining, DNA fragmentation, and changes in bcl-2 mRNA levels have been associated with this metabolic impairment. We wish to further elucidate the apoptotic cascade in this model of HD pathogenesis. 3-NP was administered to rats intraperitoneally at 20mg/kg/day for up to 3 days. At 3 days, characteristic behavioral and morphological effects became evident. While cell death did not become apparent within the first 3 days, there were changes in the levels of apoptotic regulatory proteins and translocation of cytochrome c. Within 24 h after 3-NP administration there were elevations in both bcl-xl and bax. However, bcl-xl protein levels quickly returned to control levels while bax levels continued to increase, resulting in a detrimental bax/bcl-xl ratio. Bax has been demonstrated to facilitate cytochrome c release by forming mitochondrial pores. We saw cytochrome c translocate from the mitochondria to the cytosol approximately 24 h after initial 3-NP administration when compared to saline-injected controls. This evidence generated using the 3-NP degeneration model may help elucidate the apoptotic cascade associated with HD neurodegeneration.

Regulation of ischemic cell death by the lipoic acid-palladium complex, Poly MVA, in gerbils.

Modulation of ischemic cell death can be accomplished via a multitude of mechanisms, such as quenching radical species, providing alternative energy sources, or altering glutamate excitation. Transient cerebral ischemia will induce apoptotic cell death selectively to hippocampal cornus ammon's field 1 of the hippocampus (CA1) pyramidal cells, while neighboring CA3 and dentate neurons are spared. Poly MVA is a dietary supplement based on the nontoxic chemotherapeutic lipoic acid-palladium complex (LAPd). LAPd is a liquid crystal that works in cancer cells by transferring excess electrons from membrane fatty acids to DNA via the mitochondria. Therefore, by its structural nature and action as a redox shuttle, it can both quench radicals as well as provide energy to the mitochondria. To understand the role of LAPd in regulating ischemic cell death, we studied Poly MVA. Male Mongolian gerbils were subjected to 5 min of bilateral carotid artery occlusion under a controlled temperature environment (37.0-38.0 degrees C). Animals were injected with physiological saline or either 30, 50, or 70 mg/kg of Poly MVA every 24 h beginning immediately after the occlusion until being sacrificed on experimental day 4. Damage was evaluated by analyzing nesting behavior and conducting blinded measures of viable CA1 lengths. All Poly MVA treatment dosages significantly (p < 0.05) reduced hippocampal CA1 damage by 72 h. Nesting scores were significantly improved after 30 and 50 mg/kg treatment but not 70 mg/kg. While nesting is usually a very accurate indicator of morphological damage, the 70 mg/kg-treated animals demonstrated excessive energy, thus ignoring the nesting material. While numerous routes offer varying degrees of CA1 neuronal survival after transient global ischemia, only the LAPd complex, which quenches radicals and provides energy to stabilize the mitochondria, offers such significant protection. Thus, the administration of Poly MVA may be a potent neuroprotective agent for victims of transient ischemic attack (TIA), cardiac arrest, anesthetic accidents, or drowning.