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1.
Neuroscience ; 159(1): 104-14, 2009 Mar 03.
Article in English | MEDLINE | ID: mdl-19135505

ABSTRACT

Sustained intracellular Ca(2+) elevation is a well-established contributor to neuronal injury following excessive activation of N-methyl-d-aspartic acid (NMDA)-type glutamate receptors. Zn(2+) can also be involved in excitotoxic degeneration, but the relative contributions of these two cations to the initiation and progression of excitotoxic injury is not yet known. We previously concluded that extended NMDA exposure led to sustained Ca(2+) increases that originated in apical dendrites of CA1 neurons and then propagated slowly throughout neurons and caused rapid necrotic injury. However the fluorescent indicator used in those studies (Fura-6F) may also respond to Zn(2+), and in the present work we examine possible contributions of Zn(2+) to indicator signals and to the progression of degenerative signaling along murine CA1 dendrites. Selective chelation of Zn(2+) with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) significantly delayed, but did not prevent the development and progression of sustained high-level Fura-6F signals from dendrites to somata. Rapid indicator loss during the Ca(2+) overload response, which corresponds to rapid neuronal injury, was also not prevented by TPEN. The relationship between cytosolic Zn(2+) and Ca(2+) levels was assessed in single CA1 neurons co-loaded with Fura-6F and the Zn(2+)-selective indicator FluoZin-3. NMDA exposure resulted in significant initial increases in FluoZin-3 increases that were prevented by TPEN, but not by extracellular Zn(2+) chelation with Ca-EDTA. Consistent with this result, Ca-EDTA did not delay the progression of Fura-6F signals during NMDA. Removal of extracellular Ca(2+) reduced, but did not prevent FluoZin-3 increases. These results suggest that sustained Ca(2+) increases indeed underlie Fura-6F signals that slowly propagate throughout neurons, and that Ca(2+) (rather than Zn(2+)) increases are ultimately responsible for neuronal injury during NMDA. However, mobilization of Zn(2+) from endogenous sources leads to significant neuronal Zn(2+) increases, that in turn contribute to mechanisms of initiation and progression of progressive Ca(2+) deregulation.


Subject(s)
Calcium/metabolism , Dendrites/metabolism , Extracellular Fluid/metabolism , Hippocampus/cytology , Pyramidal Cells/cytology , Zinc/metabolism , Animals , Chelating Agents/pharmacology , Dendrites/drug effects , Edetic Acid/pharmacology , Ethylenediamines/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Extracellular Fluid/drug effects , In Vitro Techniques , Male , Mice , N-Methylaspartate/pharmacology , Polycyclic Compounds/metabolism , Pyramidal Cells/drug effects , Time Factors
2.
Article in English | MEDLINE | ID: mdl-11728165

ABSTRACT

Milk was collected from 36 Nepalese women, 15 to 32 years of age, in order to investigate relationships between the proportions of intermediate chain-length (C10-C14) fatty acids and critical n-3 and n-6 polyunsaturated fatty acids in the milk lipids they were producing. Serum was also obtained from these lactating women and the fatty acid composition of their serum phospholipid fraction was determined and compared with that of the corresponding milk lipid fraction. Compared to women in technologically advanced parts of the world, the serum phospholipids of the Nepalese women contained nutritionally adequate proportions of linoleic acid (LA) (16.8%), alpha-linolenic acid (ALA) (0.53%), arachidonic acid (AA) (5.69%), and docosahexaenoic acid (DHA) (1.42%). However, although the milk lipids contained adequate proportions of ALA (1.81%), AA (0.43%), and DHA (0.23%), the lipids contained low to moderate percentages of LA (mean, 9.05%). Positive correlations were observed between the proportions of AA (P=0.001, r=0.50) and ALA (P=0.03, r=0.36) in the serum phospholipids and milk lipids of the women. As the proportion of C10-Cl4 fatty acids in the milk lipids increased from 10% to 40%, there was preferential retention of three critical n-3 and n-6 fatty acids (ALA, AA, and DHA) at the expense of two relatively abundant nonessential fatty acids, namely stearic acid and oleic acid. In addition, using fatty acid melting point data and the mol fraction of the 9 most abundant fatty acids in the milk, we estimated the mean melting point (MMP) of the milk lipids of the Nepalese women. The MMPs ranged from 29.3 to 40.5 degrees C (median, 35.5 degrees C). These results indicate that: 1) the levels of AA and ALA in the blood of lactating mothers influence the levels of these fatty acids in the milk they produce; 2) when the mammary gland produces a milk that is rich in C10-Cl4 fatty acids, it somehow regulates triglyceride synthesis in such a way as to ensure that the milk will provide the exclusively breast-fed infant with the amounts of the critical n-3 and n-6 fatty acids it requires for normal growth and development; and 3) the melting point of the milk lipid fraction is determined mainly by the mol % of the intermediate chain-length (C10-C14) fatty acids, oleic acid, linoleic acid, and alpha-linolenic acid.


Subject(s)
Fatty Acids/analysis , Lipids/chemistry , Milk, Human/chemistry , Phospholipids/blood , Phospholipids/chemistry , Adolescent , Adult , Fatty Acids/chemistry , Fatty Acids, Essential/analysis , Fatty Acids, Omega-3/analysis , Fatty Acids, Omega-6 , Fatty Acids, Unsaturated/analysis , Female , Humans , Linoleic Acid/analysis , Nepal , Nutritional Status , Oleic Acid/analysis , Palmitic Acid/analysis , Stearic Acids/analysis , Temperature , alpha-Linolenic Acid/analysis
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