Modulation of oxidative events by multivalent manganese complexes in brain tissue.

Manganese toxicity can evoke neuropsychiatric and neuromotor symptoms, which have frequently been attributed to profound oxidative stress in the dopaminergic system. However, the characterization of manganese as a pro-oxidant remains controversial because antioxidant properties also have been associated with this metal. The current study was designed to address these disparate findings concerning the oxidative properties of manganese. The apparent ability of manganese in its divalent form to promote formation of reactive oxygen species (ROS) within a cortical mitochondrial-synaptosomal (P2) fraction was completely abolished by the addition of one five hundredth of its molarity of desferroxamine (DFO), a trivalent metal chelator. This large ratio and the high specificity of DFO for trivalent metal ions discounted the possibility of inhibition of ROS generation by direct sequestration of divalent manganese, and implied the trace presence of a trivalent metal. Further analysis suggested that this trace metal was manganic rather than ferric ion. Ferric ion was able to dampen the reactive oxygen species-generating capacity of manganous chloride, whereas manganic ion markedly promoted this property attributed to manganous ion. Such findings of the potent effects of trace amounts of trivalent cations upon Mn2+-related free radical generation offer resolution of earlier disparate findings concerning the oxidative character of manganese.

Purification of follicular regulatory protein: possible plasminogen identity.

A partially purified protein (the SR fraction) of porcine and human origin has been extensively characterized as Follicular Regulatory Protein (FRP). In the current study, 1A8D5, one of several monoclonal antibodies raised against FRP, was used to further purify the protein. The monoclonal antibody cross-reacted only with porcine plasminogen, a key fibrinolytic proenzyme. A commercial polyclonal antibody for human plasminogen confirmed the relationship between plasminogen and bands of the SR fraction of the porcine follicular fluid. Sequencing of the N-terminal amino acids (54 kd) of the SR fraction indicated that it shared 100% identity with the short form of porcine plasminogen chain A and 93% identity to human plasminogen. Moreover, we demonstrated that this purified protein from human follicular fluid inhibited aromatase activity of granulosa cells, a key biological property of FRP. Given that plasminogen possesses most of the proposed properties of the protein termed FRP, we conclude that FRP is likely plasminogen itself or a plasminogen-related protein and not a novel protein.

Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neurodegeneration.

Aluminum is highly oxophilic and its minerals are usually found surrounded by six oxygen atoms. A role for the metal has been established in dialysis encephalopathy and Al-induced osteomalacia. The metal has been implicated in Alzheimer's disease but the issue is at present controversial. Human cell lines of neural origin were utilized to study the effect of lipophilic aluminum acetylacetonate and non-lipophilic aluminum sulfate on cell proliferation and viability. Although analysis of Al species in the cell culture media demonstrated that there are positively charged Al species present in solutions prepared with both Al salts, only the aluminum acetylacetonate salt caused changes in cell proliferation and viability. Therefore, the lipophilic nature of the organic Al salt is a critical determinant of toxicity. The effect of aluminum acetylacetonate was dose-dependent and time-dependent. Neuroblastoma (SK-N-SH) cells were more susceptible to decreased cell proliferation although the lipophilic Al salt was more toxic to the glioblastoma (T98G) cells. While the toxicity of aluminum acetylacetonate was inhibited in the T98G cells by the addition of phosphate, the same treatment did not reverse cell death in the SK-N-SH cells. Thus, the mechanism of Al toxicity appears to be different in the two cell lines. It is possible that the principal neurotoxic target of the metal is glial and when these cells are in a compromised state, this may secondarily impact the neuronal population and thus eventually lead to neurodegeneration.

The chemistry of transition metals in relation to their potential role in neurodegenerative processes.

Cells rely on several transition metals to regulate a wide range of metabolic and signaling functions. The diversity and efficiency of their physiological functions are derived from atomic properties that are specific to transition metals, most notably an incomplete inner valence subshell. These properties impart upon these elements the ability to fluctuate among a variety of positively charged ionic forms, and a chemical flexibility that allows them to impose conformational changes upon the proteins to which they bind. By this means, transition metals can serve as the catalytic centers of enzymes for redox reactions including molecular oxygen and endogenous peroxides. This review addresses the consequences of the aberrant translocation of the redox-capable essential transition elements, iron, copper, and manganese, upon the brain with an emphasis on uncontrolled and deleterious oxidative events. The potential of metal-protein interactions in facilitating such events, and their association with the physiologically redox-inert metals zinc and aluminum, are related to their postulated contribution to the pathology of neurodegeneration.