Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment.

TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS

Alterations in the function of the RNA-binding protein TDP-43 are largely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease of the human motor system that leads to motoneurons degeneration and reduced life expectancy by molecular mechanisms not well known. In our previous work, we found that the expression levels of the glutamic acid decarboxylase enzyme (GAD1), responsible for converting glutamate to γ-aminobutyric acid (GABA), were downregulated in TBPH-null flies and motoneurons derived from ALS patients carrying mutations in TDP-43, suggesting that defects in the regulation of GAD1 may lead to neurodegeneration by affecting neurotransmitter balance. In this study, we observed that TBPH was required for the regulation of GAD1 pre-mRNA splicing and the levels of GABA in the Drosophila central nervous system (CNS). Interestingly, we discovered that pharmacological treatments aimed to potentiate GABA neurotransmission were able to revert locomotion deficiencies in TBPH-minus flies, revealing novel mechanisms and therapeutic strategies in ALS.

TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila brains

ABSTRACTAlterations in the function of the RNA-binding protein TDP-43 is largely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease of the human motor system that leads to motoneurons degeneration and reduced life expectancy by molecular mechanisms not well known. Regarding to that, we found that the expression levels of the glutamic acid decarboxylase enzyme (GAD1), responsible to convert glutamate to γ-aminobutyric acid (GABA), were downregulated in TBPH-null flies and motoneurons derived from ALS patients carrying mutations in TDP-43 suggesting that defects in the regulation of GAD1 may lead to neurodegeneration by affecting neurotransmitter balance. In this study, we observed that TBPH was required to regulate GAD1 pre-mRNA splicing and GABA levels in Drosophila brains. Interestingly, we discovered that pharmacological treatments aimed to modulate GABA neurotransmission were able to revert locomotion deficiencies in TBPH-minus flies revealing novel mechanisms and therapeutic strategies in ALS.

INFLUENCE OF CHRONIC NEUROGENIC PAIN ON BRAIN NEUROTRANSMITTER SYSTEMS OF MALE MICE IN DYNAMICS OF MELANOMA GROWTH

Biogenic amines (BA) are known to be involved in the malignant growth, and their levels change in the CNS when exposed to pain; however, the combined effect of chronic pain and cancer on the BA dynamics in the brain has not been studied. The aim of the study was to evaluate characteristics of BA balance in the brain cortex during melanoma growth with chronic neurogenic pain (CNP). Material and methods. The study included 64 male C57Bl/6 mice weighing 22-24 g. В16/F10 melanoma was transplanted under the skin of the back to animals of the main group 2 weeks after the sciatic nerve ligation. Mice with melanoma without pain were the comparison group. Levels of BA: adrenaline, noradrenaline, dopamine (DA), serotonin (5-HT), histamine, and 5-HIAA were determined by ELISA. Results. Changes in adrenaline levels were registered in the brain of mice with CNP. The growth of melanoma in males was accompanied by elevated brain levels of adrenaline and noradrenaline and decreased dopamine and serotonin. Similarities in the direction of shifts in the neurotransmitter profile were observed in melanoma development with and without CNP. Conclusions. The influence of CNP on the neurotransmitter balance in the CNS was probably one of the factors that influenced the course of transplanted B16/F10 melanoma in males of the main group.

Biochemical Mechanisms of Hepatic Encephalopathy

Although there are similarities between the encephalopathy of acute hepatic failure and that due to cirrhosis, it is clear that some of the biochemical abnormalities arise in different ways and the relative roles of the various factors contributing to the production of encephalopathy may differ. in addition, in fulminant hepatic failure, changes in the permeability of the blood—brain barrier may enhance the effects of biochemical abnormalities and this may also be important in the genesis of cerebral oedema, which commonly complicates this form of encephalopathy. When considering encephalopathy complicating cirrhosis, it is important to recognize that the latter can be precipitated by a variety of insults each of which may lead to encephalopathy. Most research has concentrated on the accumulation in the blood of ‘toxic’ substances normally metabolized by the liver. Although no single toxin has yet been identified which alone can be responsible for hepatic encephalopathy, excess ammonia, mercaptans, fatty acids and an abnormal plasma amino acid profile have been incriminated in its pathogenesis. Irrespective of the ‘toxin’, three main pathogenetic mechanisms have been proposed to account for its action: (a) disturbed brain energy metabolism, (b) deranged neurotransmitter balance, (c) direct effects on neuronal membranes. These mechanisms are not regarded as mutually exclusive but have their final common effect of interrupting normal neurotransmission.