In children and adolescents, epilepsy is a chronic disease characterized by the paroxysmal onset of seizures resulting from abnormal cellular excitability. Idiopathic epilepsy is a disease of apparent spontaneous origin whose cause or mechanism is unknown. This opinion review describes the pathogenetic mechanisms behind epilepsy, as well as its generating and aggravating factors. A triggering factor is perinatal pain that generates amyloid-β (Aβ) oligomers that is not completely eliminated. An aggravating factor is a deficiency of DHA — due to diet or specific FADS2 alleles (Δ6-desaturase gene) — which is a preferential ligand of the PPARα-RXRα and PPARɣ-RXRα heterodimers. These two factors have impacts on the glutamatergic pathways: (i) metabolic homeostasis as a function of stimulation (regional blood flow); (ii) flow rate of GLUT-1 transporters (glucose, ascorbic acid precursor); (iii) regulation of oxidative stress; (iv) repair of oxidative injuries; (v) priority given to the non-amyloidogenic pathway; (vi) proteolysis of Aβ residues and their removal. The originality of this approach resides in particular in highlighting the fundamental role played by DHA. Understanding the risk factors can help prevent epilepsy onset, decrease epilepsy prevalence in children and adolescents and aid healthcare professionals in identifying high-risk populations and making plausible preventive nutritional measures based on DHA supplementation very early.
Neurons have high energy needs, requiring a continuous supply of glucose from the blood. Tight regulation of glucose metabolism in response to stimuli is essential for brain physiology. Glucose metabolism and cerebral blood flow are closely coordinated during neuronal activity to maintain proper brain function. In a previous article, we have already detailed the mechanisms by which the PI3K/Akt signaling pathway is involved in the efficiency of glucose uptake by stimulating GLUT-1 action and NO-mediated vasodilation. In this article, we now clarify how the activation of BDNF helps to stimulate the IRS-1/PI3K/Akt signaling pathway and upregulates NMDA receptor activity. In short, high-frequency neuronal activity induces the secretion of BDNF, whose presence boosts this important pathway. DHA, via the PPARα-RXRα and PPARɣ-RXRα heterodimers, is involved in the critical regulation of BDNF activation. As a preferential ligand of PPARs and RXRα, DHA plays an important role in the gene expression of CREB and CPE, and it is involved in the regulation and expression of tPA, as well as the inhibition of PAI-1. BDNF boosts the IGF-1/estradiol/PI3K/Akt signaling pathway, and DHA boosts the action of BDNF.
In the early stages of sporadic Alzheimer's disease (SAD), there is a strong correlation between memory impairment and cortical levels of soluble amyloid-β peptide oligomers (Aβ). It has become clear that Aβ disrupt glutamatergic synaptic function, which can in turn lead to the characteristic cognitive deficits of SAD, but the actual pathways are still not well understood. This opinion article describes the pathogenic mechanisms underlying cerebral amyloidosis. These mechanisms are dependent on the amyloid precursor protein and concern the synthesis of Aβ peptides with competition between the non-amyloidogenic pathway and the amyloidogenic pathway (i.e. a competition between the ADAM10 and BACE1 enzymes), on the one hand, and the various processes of Aβ residue clearance, on the other hand. This clearance mobilizes both endopeptidases (NEP, and IDE) and removal transporters across the blood-brain barrier (LRP1, ABCB1, and RAGE). Lipidated ApoE also plays a major role in all processes. The disturbance of these pathways induces an accumulation of Aβ. The description of the mechanisms reveals two key molecules in particular: (i) free estradiol, which has genomic and non-genomic action, and (ii) free DHA as a preferential ligand of PPARα-RXRα and PPARɣ-RXRα heterodimers. DHA and free estradiol are also self-regulating, and act in synergy. When a certain level of chronic DHA and free estradiol deficiency is reached, a permanent imbalance is established in the central nervous system. The consequences of these deficits are revealed in particular by the presence of Aβ peptide deposits, as well as other markers of the etiology of SAD.
Clostridium botulinum is a Gram -positive, strict anaerobic, rod -shaped, spore -forming, SOD -positive and catalase -negative bacterium. Its antioxidant defenses are not suited to chronic oxidative stress. H₂O₂ and reactive oxygen species have deleterious effects on C. botulinum. Spore germination is one of the key steps in its development. However, the mechanisms that trigger this germination have yet to be described. To manage C. botulinum growth, it is essential to understand the mechanisms that underlie the germination process. In this article, a series of complementary cascade reactions with water -dissolved CO₂ as an initiating germinant, and bicarbonate is suggested. It seems clear that ATP production is achieved through the use of various anaplerotic reactions with dissolved CO₂ as the carbon source. In addition to the production of oxaloacetate, an intermediate metabolite pyruvate would also be synthesized. Pyruvate would initiate the second phase of germination by producing hydrogen, which is a powerful reducing agent, via two enzymes (pyruvate -ferredoxin oxidoreductase and ferredoxin hydrogenase). These conditions would activate proteolytic enzymes and would reduce and would break the disulfide bridges of the proteins that make up the spore coats, thereby opening them. Thus, the phosphoenolpyruvate -pyruvate -acetyl -CoA pathway, in the presence of CO₂, would play a major role in the germination of spores of C. botulinum.
Neurons have a high energy need, requiring a continuous supply of glucose from the blood. Tight regulation of glucose metabolism in response to stimuli is essential for brain physiology. Glucose metabolism and cerebral blood flow are closely coordinated during neuronal activity to maintain proper brain function. Glucose uptake across the blood-brain barrier is facilitated by a carrier protein: the GLUT-1 transporter. The first way the body meets urgent demand for glucose is to increase the blood flow through vasodilatory responses generated by nitric oxide. If that is insufficient, the second way is to increase the density of GLUT-1 through the translocation of this transporter from intracellular stores. The third pathway is to increase GLUT-1 synthesis by stimulating SLC2A1 (GLUT-1 gene) transcription. A tandem of two key molecules, free estradiol and DHA, is involved in this critical regulation. Their relationship is synergistic and reciprocal: free estradiol with genomic and non-genomic actions via ERα, and DHA via the PPARα-RXRα and PPARɣ-RXRα heterodimers. We highlight several original mechanisms linking two main principles (neuronal stimulation and brain energy metabolism) with the fundamental roles played by DHA and free estradiol. In particular, it has been shown that from a certain level of chronic DHA deficiency, a permanent imbalance sets in with disturbances in glucose intake and brain metabolism. This DHA deficiency is an aggravating factor in some neuropathologies.
