Estrogen, Glutamate, & Free Fatty Acids

Also see:
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)
Phospholipases, PUFA, and Inflammation
Brain Swelling Induced by Polyunsaturated Fats (PUFA)
Women, Estrogen, and Circulating DHA
Arachidonic Acid’s Role in Stress and Shock
Estrogen’s Role in Seizures
The Brain – Estrogen’s Harm and Progesterone’s Protection
PUFA Kill Thymocytes
PUFA Breakdown Products Depress Mitochondrial Respiration
PUFA, Fish Oil, and Alzheimers
Fish Oil Toxicity
Benefits of Aspirin

“Estrogen increases the activity of the excitatory transmitter glutamate (Weiland, 1992), and glutamate increases the release of free fatty acids (Kolko, et al., 1996). DHA (more strongly even the arachidonic acid) inhibits the uptake of the excitotoxic amino acid aspartate, and in some situations glutamate, prolonging their actions.” -Ray Peat, PhD

“Albumin, besides maintaining blood volume and preventing edema, serves to protect respiration, by binding free fatty acids. Estrogen blocks the liver’s ability to produce albumin, and increases the level of circulating free fatty acids. Free fatty acids cause brain edema. This is probably another aspect of estrogen’s contribution to seizure susceptibility.” -Ray Peat, PhD

Endocrinology. 1992 Dec;131(6):2697-702.
Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus.
Weiland NG.
Ovarian steroids modulate learning, memory, and epileptic seizure activity, functions that are mediated in part by the hippocampus. Normal function depends on precise interactions between the inhibitory gamma-aminobutyric acid (GABA)ergic and excitatory glutamatergic neurons of the hippocampus. To determine whether estradiol and progesterone interact with GABAergic neurons, the levels of mRNA for glutamic acid decarboxylase (GAD), the rate-limiting enzyme for GABA synthesis, were measured by in situ hybridization histochemistry with 35S-labeled riboprobes complimentary to the feline GAD cDNA. The levels of mRNA for GAD were analyzed in selected region of the dorsal hippocampus and medial basal hypothalamus in ovariectomized, ovariectomized estradiol-treated, and ovariectomized estradiol- and progesterone-treated rats. In estradiol-treated rats, GAD mRNA levels increased in GABAergic neurons associated with the CA1 pyramidal cell layer, but not in the stratum oriens of CA1 or any other region of the hippocampus. Estradiol plus progesterone treatment reversed the estradiol-induced increase in GAD mRNA in CA1 and induced a small decrease in the hilus. No effect of estradiol or progesterone was observed in the dorsomedial, ventromedial, or arcuate nuclei of the hypothalamus. Estradiol or progesterone may alter cognitive performance and seizure activity by increasing or decreasing, respectively, the activity of GABAergic neurons in the hippocampus.

J Biol Chem. 1996 Dec 20;271(51):32722-8.
Synergy by secretory phospholipase A2 and glutamate on inducing cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal cultures.
Kolko M, DeCoster MA, de Turco EB, Bazan NG.
Secretory and cytosolic phospholipases A2 (sPLA2 and cPLA2) may contribute to the release of arachidonic acid and other bioactive lipids, which are modulators of synaptic function. In primary cortical neuron cultures, neurotoxic cell death and [3H]arachidonate metabolism was studied after adding glutamate and sPLA2 from bee venom. sPLA2, at concentrations eliciting low neurotoxicity (Synergy in neurotoxicity and [3H]arachidonate release was observed when low, nontoxic (10 ng/ml, 0.71 nM), or mildly toxic (25 ng/ml, 1. 78 nM) concentrations of sPLA2 were added together with glutamate (80 microM). A similar synergy was observed with the sPLA2 OS2, from Taipan snake venom. The NMDA receptor antagonist MK-801 blocked glutamate effects and partially inhibited sPLA2 OS2 but not sPLA2 from bee venom-induced arachidonic acid release. Thus, the synergy with glutamate and very low concentrations of exogenously added sPLA2 suggests a potential role for this enzyme in the modulation of glutamatergic synaptic function and of excitotoxicity.

Increased intracellular calcium activates lipolysis (by phospholipases), producing more free fatty acids, as well as excitation and protein breakdown, and in the brain neurodegenerative diseases, calcium excess contributes to clumping synuclein (Wojda, et al., 2008), an important regulator of cytoskeleton proteins. -Ray Peat, PhD

IUBMB Life. 2008 Sep;60(9):575-90.
Calcium ions in neuronal degeneration.
Wojda U, Salinska E, Kuznicki J.
Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.

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