Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in “Long-COVID19”

[SWAlexander]

Highlights

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Combined treatment with the α2A-adrenoceptor agonist, guanfacine, and the anti-oxidant, N-acetylcysteine (NAC) reduced the cognitive deficits (“brain fog”) associated with long-COVID19 in eight out of twelve patients.
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Two patients stopped treatment due to hypotension and/or dizziness, common side effects of guanfacine, and two patients were lost to follow-up.
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The remaining eight patients reported improved working memory, concentration and executive function, including the resumption of normal workloads.
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One patient temporarily stopped guanfacine due to a hypotensive episode and reported a return of cognitive deficits that abated with resumed guanfacine treatment.
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Although placebo-controlled trials will be needed to demonstrate efficacy, the established safety of guanfacine and NAC suggests they may be immediately useful in treating the cognitive deficits of long-COVID19.

Abstract
Background
Prolonged cognitive deficits (“brain fog”) following COVID19 infection (long-COVID) are common and debilitating, yet there are currently no approved treatments. Cognitive impairment particularly targets the working memory and executive functions of the prefrontal cortex (PFC). The PFC has unusual neurotransmission and neuromodulation that render it vulnerable to stressors, and basic research has identified mechanisms that protect PFC connections. Based on the basic neuroscience data, we tried a combined open label treatment to bolster prefrontal function: the α2A-adrenoceptor agonist, guanfacine, which strengthens prefrontal connectivity, and the anti-oxidant, N- acetylcysteine (NAC), which protects mitochondria and reduces kynurenic acid blockade of NMDA receptors.
https://www.sciencedirect.com/science/article/pii/S2667257X22001000

Article also at:
Potential New Treatment for “Brain Fog” in Long COVID Patients
https://medicine.yale.edu/news-article/potential-new-treatment-for-brain-fog-in-long-covid-patients/

 

[pattismith]

I am interested in the Guanfacine effect on the brain.

It was shown to have several effects on brain blood flow

- decreased intracranial pressure
- increased blood flow in the frontal cortex
- decreased blood flow in the posterior temporal-occipital cortex
- decreased cerebral blood flow in striatum (rats)

Guanfacine produces differential effects in frontal cortex compared with striatum: assessed by phMRI BOLD contrast | SpringerLink

The Effects of an Alpha-2 Adrenergic Agonist, Guanfacine, on rCBF in Human Cortex in Normal Controls and Subjects with Focal Epilepsy | Neuropsychopharmacology (nature.com)

 

[Violeta]

Guanfacine did help with neurological symptoms but it causes a drop in blood pressure.

Butcher's Broom is an alpha-2adrenergic receptor agonist, too, but doesn't drop blood pressure. In fact, it helps maintain blood pressure.

Ruscus aculeatus is an alpha-adrenergic agonist that causes venous constriction by directly activating postjunctional alpha1- and alpha2-receptors, in turn stimulating the release of noradrenaline at the level of the vascular wall.

It also possesses venotonic properties: it reduces venous capacity and pooling of blood in the legs and exerts protective effects on capillaries, the vascular endothelium, and smooth muscle. Its flavonoid content strengthens blood vessels, reduces capillary fragility, and helps maintain healthy circulation.

Unlike most of the drug therapies used to treat OH, Ruscus aculeatus does not cause supine hypertension. It also appears to do something no other therapy can offer--alleviate the worsening effects of OH in environmentally hot conditions. Finally, it is an extremely safe, inexpensive, over-the-counter botanical medicine.

https://pubmed.ncbi.nlm.nih.gov/11152059/

Ruscus aculeatus (butcher's broom) as a potential treatment for orthostatic hypotension, with a case report

D A Redman 1

 

[pattismith]

Maybe Ruscus could prevent Guanfacine associated hypotension?

It looks like the interesting effect of Guanfacine is in the brain (central) whereas the interesting effect of Ruscus is peripheral (systemic)

CV Pharmacology | Alpha-Adrenoceptor Agonists (α-agonists)

PulmCrit- Alpha-2 agonists: clonidine, guanfacine, lofexidine, and KetaDex (emcrit.org)

 

[Violeta]

@pattismith, can you see anything about the Butcher's Broom's a2A-adrenergic receptor info that would make it not do what guanfacine does?

 

[pattismith]

@pattismith, can you see anything about the Butcher's Broom's a2A-adrenergic receptor info that would make it not do what guanfacine does?

There are 3 alpha2 receptors subtypes: A, B and C

α2A-receptors decrease sympathetic outflow and blood pressure, whereas the α2B-subtype increases blood pressure.
Other biological functions are regulated by synergistic α2-receptor subtypes.
The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, α2A and α2C.

Ruscus doesn't produce sedation nor hypotension nor bradycardia like Clonidine, Dexmedetomidine or Guanfacine, that all activate the alpha2A receptor, so we can speculate Ruscus doesn't activate this particular receptor, and that it is more specific of the alpha2B receptor;
Did you find any effect Ruscus has on heart rate?

At lower doses alpha 2-adrenergic agonists produce hypotension by inhibition of the firing of the locus coeruleus in the brain stem and decreasing norepinephrine release at synapse. (note this is the result of alpha 2A recptor activation)
At higher doses hypertension can be induced via the activation of alpha 2B adrenoceptors located on smooth muscle cells in the resistance vessels.

(PDF) Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia (researchgate.net)

Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

(PDF) Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia (researchgate.net)

 

[pattismith]

Maybe this combined treatment an option for some ME/CFS patients? It might avoid Ganfacine hypotension

Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder - PubMed (nih.gov)

 

[Violeta]

There are 3 alpha2 receptors subtypes: A, B and C



Ruscus doesn't produce sedation nor hypotension nor bradycardia like Clonidine, Dexmedetomidine or Guanfacine, that all activate the alpha2A receptor, so we can speculate Ruscus doesn't activate this particular receptor, and that it is more specific of the alpha2B receptor;
Did you find any effect Ruscus has on heart rate?





(PDF) Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia (researchgate.net)
View attachment 50395
Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology



View attachment 50396

(PDF) Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia (researchgate.net)

Wow, thank you Patti, that makes sense.

With respect to my heart rate, I find that it stops the fluttering feeling.