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Has anyone tried ACE2 blockers or modulators in an attempt to upregulate ACE 2?

Posted: Wed May 17, 2023 11:44 pm
by Terabithia
I’m sure many of you have seen the Celltrend results of a few PSSD sufferers showing ACE2 antibodies. An interesting paper I read also made the claim that “ACE2 deficiency affects the levels and actions of the neurotransmitters serotonin, dopamine, norepinephrine, GABA, and glutamate which play crucial roles in adult neurogenesis.” The levels of neurotransmitters were reduced in the studies. This may be a fruitful avenue to pursue. I will link the text below. I will also link a paper that explores natural ACE2 modulators. Some of them are well known substances like Licorice Root, Ginseng, Omega 3 fatty acids, and Apigenin among others.

ACE2 and neurotransmitters:

Celltrend Results: ... ame=iossmf

Natural ACE2 modulators: ... 29935/full

“There are many common compounds that can increase the expression of the ACE2 receptor including Vitamin C, Metformin, Resveratrol, Vitamin B3 and Vitamin D.
https://clinicalhypertension.biomedcent ... itamin%20D.

Excerpt of text:

ACE2 and neurotransmitters involved in adult neurogenesis

Neurotransmitter signalling is found to play a major role in the formation of new neurons in addition to its clear and indisputable role in communication between neurons. Starting from embryogenesis, neurotransmitters are involved in neuronal proliferation. In adult neurogenesis, they influence various steps including proliferation, differentiation, and migration. In addition to the direct action of neurotransmitters on adult neurogenesis, they also influence other factors that regulate neurogenesis like neurotrophic factors and growth factors [107].

9.1 ACE2 and serotonin

Serotonin is a crucial monoaminergic neurotransmitter that acts as a mood stabiliser and is associated with feelings of happiness, well-being, and contentedness. In the brain, it is synthesised by the Raphe nuclei neurons in the brain stem from tryptophan using neuron-specific tryptophan hydroxylase 2 enzymes. Vesicular monoamine transporter 2 [VMAT] packs the synthesised serotonin into vesicles. Serotonin transporters [SERT] re-uptake serotonin back to presynaptic neurons after its release, thereby regulating its extracellular levels [108]. The serotonergic fibres from raphe nuclei have projections throughout the brain and especially to the granule cells and interneurons of the dentate gyrus of the hippocampus. Serotonin is known to play a major regulatory role in adult hippocampal neurogenesis. Selective serotonin reuptake inhibitors [SRRI] are commonly used antidepressants that act by increasing serotonin levels in the brain causes clinical improvement associated with an increase in adult hippocampal neurogenesis characterised by increased neuronal proliferation and number of newborn neurons [109]. Malberg et al. in 2000 were the first to show that chronic treatment with fluoxetine improved adult hippocampal neurogenesis [109]. In the dentate gyrus, serotonin is known to promote neuronal development and its depletion was found to cause reduced dendritic spine density of granule cells [110, 111, 112, 113]. Chronic treatment with SSRI, fluoxetine was found to increase the survival of newborn neurons in the dentate gyrus [109, 114]. In stress models like inescapable stress, cold restraint stress in the animal model, fluoxetine administration was found to exhibit neurogenic and neuroprotective roles in the hippocampus [114, 115]. Accelerated synaptogenesis and increased long-term potentiation [LTP] in the hippocampus were also observed by long-term treatment by fluoxetine [116].

Recent studies have found that ACE2 plays a major role in the biosynthesis of serotonin [5HT]. The precursor for 5HT is an essential amino acid, tryptophan which can cross the blood–brain barrier and whose intestinal absorption was found to be reduced by 70% in case of ACE2 deficiency. Thus, ACE2 has an indirect modulatory role in 5HT synthesis in the brain [117]. There are recent studies that show that 5HT synthesis in the brain is dependent on ACE2, which acts by modulating 5HT metabolism and ACE2 deficiency leads to decreased serum tryptophan levels and decreased serotonin levels in the brain [94].

9.2 ACE2 and dopamine

Dopamine is involved in executive functions, volition, motor control, motivation, pleasure/reward, and attention/concentration [118]. The role and mechanism of action of dopamine in adult neurogenesis are not elucidated fully. Dopamine was found to modulate cell proliferation in the embryonic brain [119]. Hippocampus and sub-ventricular zone [SVZ] which are the neurogenic niche containing neural stem cells receive dopaminergic projections from the substantia nigra and ventral tegmental area. Dopamine receptors are also widely expressed in these two areas and play a regulatory role in adult neurogenesis and neural plasticity [120, 121]. Earlier studies show that depletion of dopamine in the rat model reduces both proliferation and survival of neural precursor cells in the sub-granular zone [SGZ] of the dentate gyrus [122, 123]. Dopaminergic denervation in substantia nigra caused a significant reduction in the proliferation of neural stem cells in SGZ and SVZ which was reversed by D2 receptor stimulation in rodents [123]. In humans, post-mortem studies have revealed that the number of neural precursor cells in SGZ and SVZ was reduced in patients with Parkinson’s disease [124]. Dopamine was also found to increase the type 2A early progenitor cell in the hippocampus of rodents via D1 like receptors [118]. Dopamine receptor agonist pramipexole increases the proliferation and survival of newborn neurons in SVZ, olfactory bulb [119].

RAS plays a major role in dopaminergic vulnerability through AT1 receptors. Dysregulation of RAS due to the downregulation of ACE2 induced by SARS-CoV-2 may increase the vulnerability of dopaminergic neurons and subsequently dopamine levels [125]. Interactions between dopamine and angiotensin receptors that are counterregulatory in nature are observed in substantia nigra and striatum [125]. The gene for ACE2 was found to coexpress and coregulate with that of dopa decarboxylase [DDC] in non-neuronal cells, which is a major enzyme of dopamine, serotonin, and histamine biosynthesis. DDC converts L-3,4-dihydroxyphenylalanine [L-DOPA] into dopamine which subsequently forms norepinephrine and epinephrine and L-5-hydroxytryptophan into serotonin. This coexpression and coregulation link between the genes for ACE2 and DDC gives rise to the possibility of a functional link between the actions of ACE2 and DDC [i.e.,] in the synthesis of Ang [1-7] and dopamine and serotonin mediated by ACE2 and DDC, respectively [126]. Following the infusion of Ang [1-7] in the hypothalamus of rats, brain dopamine levels increased which emphasises the link between ACE2 and DDC. SARS-CoV-2 induced downregulation of ACE2 could cause the decreased synthesis of serotonin and dopamine [94, 127].

The SARS-CoV-2 infection has been found to cause loss of dopaminergic neurons and deficits in the dopamine system [86, 128]. ACE2 expression is high in dopaminergic neurons and the downregulation of ACE2 by SARS-CoV-2 may cause depletion of dopaminergic neurons and dopamine levels. This is evident from the worsening of symptoms observed in COVID-19 patients with Parkinson’s disease [PD], requiring increased dopamine replacement therapy [129]. ACE2 deletion in the knockout mouse model caused a significant reduction in dopamine D1 mRNA expression in substantia nigra [130].

9.3 ACE2 and norepinephrine

Norepinephrine is an important catecholamine that is involved in alertness, arousal, sleep–wake cycle, memory storage, and emotions. It modulates various functions of the hippocampus like learning, memory, and mood. Noradrenergic axon terminals arising from the locus coeruleus densely innervate the neurogenic niche in the adult hippocampus [131]. Norepinephrine along with the other monoaminergic neurotransmitters plays a major role in adult neurogenesis. Norepinephrine was found to activate the stem cells and neural precursor cells via β3-adrenergic receptors where non-proliferating latent precursor cells develop the ability to respond to mitogens and generate neurospheres. It also increases the proliferation of early progenitor cells in the adult hippocampus via β2-adrenergic receptors [132, 133]. Depletion of norepinephrine significantly decreased the proliferation of progenitor cells of granule cells in the hippocampus [134]. Antidepressants that selectively increase norepinephrine were found to increase adult hippocampal neurogenesis [132].

Downregulation of ACE2 by SARS-CoV-2 may affect the activity of DDC due to the coexpression and coregulation between the genes for ACE2 and DDC. This could lead to a decrease in the biosynthesis of dopamine and subsequently norepinephrine [126].

9.4 ACE2 and glutamate and GABA

Glutamate is the predominant excitatory neurotransmitter of the CNS. It plays a vital role in both embryonic brain development and adult neurogenesis. Its extracellular levels are especially higher in the neurogenic niche when compared to other areas of the brain [135, 136]. It has trophic effects on the developing neurons before synapse formation like proliferation, migration, and maturation. It causes an increase in the proliferation of neural progenitor cells [NPC]. The NPCs express NMDA metabotropic glutamate receptors, stimulation of which caused increased intracellular calcium and activation of NeuroD1, proneural gene [137]. Glutamate signalling plays a positive role in maintaining the proliferation of NPCs and the survival rates of newborn neurons [137, 138].

Gamma-aminobutyric acid [GABA] is a principal inhibitory neurotransmitter in the CNS. It is produced from glutamate by the action of the enzymes glutamate decarboxylase GAD65 and GAD67 [139]. Dysfunction in the GABAergic system is implicated in major depressive disorder and anxiety [140]. However, in the developing brain, GABA exerts an excitatory effect, that is, GABA is excitatory in immature neurons. Tonic discharge from GABAergic neurons is necessary for maintaining the quiescent state of NPCs. The absence of GABAergic excitability will cause impairment in neuronal maturation and synapse formation while an excess of it over newborn neurons will lead to seizures [141]. In SGZ, GABA mediates depolarisation of progenitor cells which is involved in the incorporation of AMPA receptors in immature granule cells, which is critical for learning and formation of memory [142]. It has a negative influence on neuroblasts. It inhibits the proliferation and migration of neuroblasts. It also inhibits the proliferation of NPCs [143, 144, 145]. It also promotes the differentiation of hippocampal NPCs. GABAA receptor agonist, phenobarbital caused a reduction in NPC proliferation and increase in differentiation which resulted in an increased number of newborn neurons [146]. Thus, it plays crucial role in different stages of adult neurogenesis. GABA and glutamate signalling play a major role in adult neurogenesis. Selective activation of the receptor subtypes of GABA and glutamate expressed in NPCs plays a pivotal role in self-replication and fate commitment of the developing neurons into a particular progeny [147].

A recent study has found ACE2 to be located mainly in excitatory neurons of the brain and to a lesser extent in inhibitory neurons like GABAergic neurons [148]. This indicates that SARS-CoV-2 once enters the brain has the potential to access the glutamatergic and GABAergic neurons. The consequence of this is not known however, viral entry may trigger apoptotic pathways and cause excitatory-inhibitory imbalance, and lead to neuronal death [149]. Cytokine release from infected neurons and other activated microglia and astrocytes may also cause a decrease in glutamate and GABA [150]. These effects are implicated along with impaired adult neurogenesis in neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease. Seizure is one of the neurological symptoms in COVID-19 patients, in which an increase in glutamate levels and decrease in GABA levels in the cerebral cortex and hippocampus is an implicated mechanism [151]. This further emphasises the possible impact of SARS-CoV-2 on glutamate and GABA.

Thus, SARS-CoV-2 induced downregulation of ACE2 in COVID-19 is potentially detrimental to adult neurogenesis. ACE2 deficiency affects the levels and actions of the neurotransmitters serotonin, dopamine, norepinephrine, GABA, and glutamate which play crucial roles in adult neurogenesis.

Re: Has anyone tried ACE2 blockers or modulators in an attempt to upregulate ACE 2?

Posted: Thu May 18, 2023 2:13 am
by AdvencedResearchPL
I tried all of this natural, none helped.

Re: Has anyone tried ACE2 blockers or modulators in an attempt to upregulate ACE 2?

Posted: Thu May 18, 2023 2:44 am
by Terabithia
It would most likely have to be taken for weeks at the proper dosages for the upregulation to take place.

Re: Has anyone tried ACE2 blockers or modulators in an attempt to upregulate ACE 2?

Posted: Thu May 18, 2023 2:50 am
by AdvencedResearchPL
they were used for a few weeks, but there will always be someone who says "it should be months "and someone else says "years".

Re: Has anyone tried ACE2 blockers or modulators in an attempt to upregulate ACE 2?

Posted: Fri May 19, 2023 9:44 am
by BlackCat
I've been using Omega 3 for years now. Tried Licorice Root and Ginseng for a couple of weeks too. No recovery.

Re: Has anyone tried ACE2 blockers or modulators in an attempt to upregulate ACE 2?

Posted: Sat May 20, 2023 4:38 am
by Impermanence
Upregulation with antagonist doesn't occur systematically (hopefully). Patients with HBP treated with ACE blockers usually don't need to increase the dosage with time so don't think blocker upregulate something.
It's true for 5HT1A AUTO-receptor but no true for all receptors...