[Paper Review] Thermodynamics and SARS-CoV-2: neurological effects in post-Covid 19 syndrome

Umberto Lucia, Giulia Grisolia+1 more|arXiv (Cornell University)|Jul 26, 2021

Long-Term Effects of COVID-1943 references17 citations

TL;DR

This paper proposes a non-equilibrium thermodynamic model linking SARS-CoV-2-induced pH disturbances to neuronal membrane potential changes via ion fluxes, particularly Na+ and K+, explaining neurological symptoms in post-COVID-19 syndrome. The key contribution is a theoretical framework suggesting that correcting electrolyte imbalances—especially Na+ and K+—could mitigate neurological sequelae by stabilizing membrane potential and restoring normal neuronal signaling.

ABSTRACT

There is increasing evidence that infection with SARS-CoV-2 can cause a spectrum of neurological symptoms. In this paper, we develop a theoretical concept underlying such neurological COVID-19 consequences by employing a non-equilibrium thermodynamic approach that allows linking the neuronal electric potential with a virus-induced pH variation. Our theoretical findings support further experimental work on therapeutically correcting electrolyte imbalances, such as Na$^+$ and K$^+$, to attenuate the neurological effects of SARS-CoV-2.

Motivation & Objective

• To investigate the underlying thermodynamic mechanisms linking SARS-CoV-2 infection to neurological symptoms in post-COVID-19 syndrome.
• To explore how viral-induced pH changes disrupt ion homeostasis and alter neuronal membrane potential.
• To propose a theoretical basis for targeting electrolyte imbalances (Na+, K+) as a therapeutic strategy to reduce neurological sequelae.
• To establish a connection between irreversible thermodynamics and neuronal signaling dysfunction in SARS-CoV-2 infection.
• To provide a mechanistic explanation for neurological symptoms such as 'brain fog,' memory loss, and olfactory dysfunction despite low viral load in the CNS.

Proposed method

• Employed non-equilibrium thermodynamics using Onsager's phenomenological relationships to model ion and heat fluxes across neuronal membranes.
• Applied the Nernst-Planck and electrochemical potential equations to describe ion transport driven by electrochemical gradients.
• Used the Gibbs free energy change (ΔG) to link pH variation to membrane potential (Δφ) via ΔpH = (F / 2.3RT)(Δφ − ΔGH+).
• Formulated the phosphorylation potential (Δḡp = −nFΔφ) to connect ATP hydrolysis to ion pumping and membrane potential maintenance.
• Integrated the H+-ATPase pump mechanism to model how proton flux alters intracellular pH and affects Na+/K+ exchange.
• Derived a thermodynamic link between pH changes and neuronal signaling via symmetry breaking in ion concentration gradients under non-equilibrium conditions.

Experimental results

Research questions

• RQ1 How does SARS-CoV-2-induced pH alteration affect neuronal membrane potential through ion fluxes?
• RQ2 What is the thermodynamic relationship between pH variation and changes in Na+ and K+ concentrations in neurons?
• RQ3 Can disruptions in ion homeostasis due to viral infection lead to measurable changes in neuronal signaling and neurological symptoms?
• RQ4 To what extent can correcting electrolyte imbalances (Na+, K+) restore normal membrane potential and reduce neurological sequelae?
• RQ5 What is the theoretical basis for using hypertonic saline or electrolyte modulation as a potential therapy in post-COVID neurological disorders?

Key findings

• A change in pH directly induces a variation in neuronal membrane potential through the electrochemical potential gradient, as described by ΔpH = (F / 2.3RT)(Δφ − ΔGH+).
• SARS-CoV-2 infection disrupts pH homeostasis, leading to altered H+ fluxes and subsequent changes in Na+ and K+ ion transport across the neuronal membrane.
• The model demonstrates that ion flux perturbations break the symmetry of stationary ion concentrations, thereby modulating neuronal signaling and potentially causing neurological symptoms.
• Theoretical analysis supports that correcting Na+ and K+ imbalances could stabilize membrane potential and attenuate neurological effects of SARS-CoV-2.
• Equation (25) suggests that potassium correction may have a particularly pronounced effect on restoring neuronal function, though clinical application requires caution.
• Theoretical findings are consistent with experimental preprints showing that hypertonic saline (1.5% NaCl) inhibits SARS-CoV-2 replication in vitro via membrane depolarization and energy depletion.