Ammonia
links: reference: 4-30-2021
Ammonia
#
- Alters the function of the BBB.
- Binds to NMDARs and can induce anxiety, restlessness, ADHD, brain fog, fatigue, “wired but tired”.
- Produced by fatigue or Liver inefficiency (and other things) creates torpor and promotes Excitotoxicity.
Hyperammonemia causes swelling of astrocytes
- Contributes to high extracellular GABAergic tone. Increases GAT-3 membrane expression.
- Hyperammonemia increases GABAergic tone in the cerebellum but decreases it in the rat cortex
- Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia
- Hyperammonemia Enhances GABAergic Neurotransmission in Hippocampus: Underlying Mechanisms and Modulation by Extracellular cGMP
-
Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum
- Hyperammonemia increased p-Ser847 on nNOS via CAMK II, reducing its activity. The CAMK activity seems to be because of some kinda tonic NMDA activation, especially considering NMDA antagonism rescues signaling of cGMP and NO metabolites from HE.
- And yet:
Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats ’nuff said in title.
- As an aside, I think rescuing cGMP will also promote Protein Kinase G which -> GluR1 p-Ser845,
- And yet:
Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats ’nuff said in title.
- Hyperammonemia increased p-Ser847 on nNOS via CAMK II, reducing its activity. The CAMK activity seems to be because of some kinda tonic NMDA activation, especially considering NMDA antagonism rescues signaling of cGMP and NO metabolites from HE.
-
Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications
- neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss
- Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA
- These alterations are reversed by treatments that reduce peripheral inflammation (anti-TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP).
-
Hyperammonemia alters the modulation by different neurosteroids of the glutamate-nitric oxide-cyclic GMP pathway through NMDA- GABAA - or sigma receptors in cerebellum in vivo (Gonzalez-Usano et al. 2013)
- In hyperammonemic rats, Allopregnanolone acts as an NMDAR antagonist. Pregnenolone somehow had no effect on controls, but in hyperammonemic rats, it is a Sigma Receptor agonist and has increased NMDA modulation - so you could just say it is potentiated.
- Hyperammonemia raises cortex levels of Allopregnanolone and THDOC 2x. In cerebellum, THDOC and pregnenolone increased 5x.
- Naturally, this anti-NMDA action inhibits LTP: Ammonia Inhibits Long-term Potentiation via Neurosteroid Synthesis in Hippocampal Pyramidal Neurons
- Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema
- Glutamine in the mechanism of ammonia-induced astrocyte swelling
-
Compromised Astrocyte Swelling/Volume Regulation in the Hippocampus of the Triple Transgenic Mouse Model of Alzheimer’s Disease
- Pax: The accumulation of glycogen within thw brain occurs as a consequence of insulin-induced glucose metabolism and expression of amylase within the brain which produces failure in Glucocerebrosidase and this leads to functional defects in autophagesome accumulation due to defects in insulin-induced mtorc2 activation (GCase+mTORC2 supports autophagosome formation)