Sadly, this research gets published after Mark Purdey has passed away.
Manganese caused "mitochondrial depolarization and ROS (reactive oxygen species) production" followed by "apoptotic cell death cascade"...
So the question is, why does manganese flood to the brain with TSEs? Answer: ROS - production of reactive oxygen species caused by ?
Do you really believe FATEPRiDE, and others, when they claim that OPs did not influence the BSE catastrophe in the UK, and elsewhere? The UK government mandated the treatment of warbles in 1982 and most farms used PHOSMET, an organophosphate, because the withdrawal time was only a matter of hours, and their dairy cattle could be treated after the morning milking and they could still sell the evening milk - ie; no waste of milk or loss of income.
Exposure to OPs, whether as a warblecide or as a spray on crops, will cause increased reactve oxygen (or nitrogen) species [ROS], thus upregulating the production of various antioxidant mechanisms, including the manganese based superoxide dismutase.
Also, radiation [ie: external or internalized] exposure also upregulates manganese SOD activity. If the internalized radiation [for example inhalation of Depleted Uranium, strontion 90, lead 210, cesium 137, etc] into the nasal cavity can cause co-localization to various parts of the brain and body, which would trigger the upregulation of manganese based SOD.
Toxicol Sci. 2007 May 4; [Epub ahead of print]
Normal Cellular Prion Protein Protects against Manganese-induced Oxidative Stress and Apoptotic Cell Death.
Choi CJ, Anantharam V, Saetveit NJ, Houk R, Kanthasamy A, Kanthasamy AG.
Neuroscience and Toxicology graduate Programs, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University.
The normal prion protein is abundantly expressed in the CNS, but its biological function remains unclear. The prion protein has octapeptide repeat regions that bind to several divalent metals, suggesting that the prion proteins may alter the toxic effect of environmental neurotoxic metals. In the present study, we systematically examined whether prion protein modifies the neurotoxicity of manganese (Mn) by comparing the effect of Mn on mouse neural cells expressing prion protein (PrP(C)-cells) and prion-knockout (PrP(KO)-cells). Exposure to Mn (10 muM-1 mM) for 24 hr produced a dose-dependent cytotoxic response in both PrP(C)-cells and PrP(KO)-cells. Interestingly, PrP(C)-cells (EC(50) 117.6muM) were more resistant to Mn-induced cytotoxicity, as compared to PrP(KO)-cells (EC(50) 59.9muM), suggesting a protective role for PrP(C) against Mn neurotoxicity. Analysis of intracellular Mn levels showed less Mn accumulation in PrP(C)-cells as compared to PrP(KO)-cells, but no significant changes in the expression of the metal transporter proteins transferrin and DMT-1. Furthermore, Mn-induced mitochondrial depolarization and ROS generation were significantly attenuated in PrP(C)-cells as compared to PrP(KO)-cells. Measurement of antioxidant status revealed similar basal levels of glutathione (GSH) in PrP(C)-cells and PrP(KO)-cells; however, Mn treatment caused greater depletion of GSH in PrP(KO)-cells. Mn-induced mitochondrial depolarization and ROS production were followed by time- and dose-dependent activation of the apoptotic cell death cascade involving caspase-9 and -3. Notably, DNA fragmentation induced by both Mn treatment and the oxidative stress inducer hydrogen peroxide (100muM) was significantly suppressed in PrP(C) -cells as compared to PrP(KO)-cells. Together, these results demonstrate that prion protein interferes with divalent metal Mn uptake and protects against Mn-induced oxidative stress and apoptotic cell death.
PMID: 17483122
Manganese caused "mitochondrial depolarization and ROS (reactive oxygen species) production" followed by "apoptotic cell death cascade"...
So the question is, why does manganese flood to the brain with TSEs? Answer: ROS - production of reactive oxygen species caused by ?
ScientificWorldJournal. 2006 Feb 28;6:295-310.
Anticholinesterase toxicity and oxidative stress.
Milatovic D, Gupta RC, Aschner M.
Department of Pediatrics, Medical School, Vanderbilt University, Nashville, TN, USA. [email protected]
Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.
PMID: 16518518
Do you really believe FATEPRiDE, and others, when they claim that OPs did not influence the BSE catastrophe in the UK, and elsewhere? The UK government mandated the treatment of warbles in 1982 and most farms used PHOSMET, an organophosphate, because the withdrawal time was only a matter of hours, and their dairy cattle could be treated after the morning milking and they could still sell the evening milk - ie; no waste of milk or loss of income.
Exposure to OPs, whether as a warblecide or as a spray on crops, will cause increased reactve oxygen (or nitrogen) species [ROS], thus upregulating the production of various antioxidant mechanisms, including the manganese based superoxide dismutase.
Also, radiation [ie: external or internalized] exposure also upregulates manganese SOD activity. If the internalized radiation [for example inhalation of Depleted Uranium, strontion 90, lead 210, cesium 137, etc] into the nasal cavity can cause co-localization to various parts of the brain and body, which would trigger the upregulation of manganese based SOD.
Acta Physiol Hung. 2006 Dec;93(4):341-6.
Regional differences in antioxidative response of rat brain after cranial irradiation.
Todorovic A, Pejic S, Kasapovic J, Stojiljkovic V, Pajovic SB, Kanazir DT.
Laboratory of Molecular Biology and Endocrinology, Vinda Institute of Nuclear Sciences, P.O. Box 522, 11000 Belgrade, Serbia.
In order to examine if differences in activity and inducibility of antioxidative enzymes in rat cerebral cortex and hippocampus are underlying their different sensitivity to radiation, we exposed four-day-old female Wistar rats to cranial radiation of 3 Gy of gamma-rays. After isolation of hippocampus and cortex 1 h or 24 h following exposure, activities of copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and catalase (CAT) were measured and compared to unirradiated controls. MnSOD protein levels were determined by SDS-PAGE electrophoresis and Western blot analysis. Our results showed that CuZnSOD activity in hippocampus and cortex was significantly decreased 1 h and 24 h after irradiation with 3 Gy of gamma-rays. MnSOD activity in both brain regions was also decreased 1 h after irradiation. 24 h following exposure, manganese SOD activity in hippocampus almost achieved control values, while in cortex it significantly exceeded the activity of the relevant controls. CAT activity in hippocampus and cortex remained stable 1 h, as well as 24 h after irradiation with 3 Gy of gamma-rays. MnSOD protein level in hippocampus and cortex decreased 1 h after irradiation with 3 Gy of gamma-rays. 24 h after exposure, MnSOD protein level in cortex was similar to control values, while in hippocampus it was still significantly decreased. We have concluded that regional differences in MnSOD radioinducibility are regulated at the level of protein synthesis, and that they represent one of the main reasons for region-specific radiosensitivity of the brain.
PMID: 17191666