Neuropsychiatric Manifestations of COVID-19 Disease and Post COVID Syndrome: The Role of N-acetylcysteine and Acetyl-L-carnitine

Abstract

COVID-19 is associated with neuropsychiatric symptoms, such as anosmia, anxiety, depression, stress-related reactions, and psychoses. The illness can cause persistent cognitive impairment and "brain fog", suggesting chronic brain involvement. Clinical entities of ongoing symptomatic COVID-19 and Post COVID Syndrome (PCS) mainly present neuropsychiatric symptoms such as dysgeusia, headache, fatigue, anxiety, depression, sleep disturbances, and post-traumatic stress disorder. The pathophysiology of COVID-19-related brain damage is unclear, but it is linked to various mechanisms such as inflammation, oxidative stress, immune dysregulation, impaired glutamate homeostasis, glial and glymphatic damage, and hippocampal degeneration. Noteworthy is that the metabotropic receptor mGluR2 was discovered as a mechanism of internalisation of SARS-CoV-2 in Central Nervous System (CNS) cells. N-acetylcysteine (NAC) and acetyl-L-carnitine (ALC) are two supplements that have already been found effective in treating psychiatric conditions. Furthermore, NAC showed evidence in relieving cognitive symptomatology in PCS, and ALC was found effective in treating depressive symptomatology of PCS. The overlapping effects on the glutamatergic system of ALC and NAC could help treat COVID-19 psychiatric symptoms and PCS, acting through different mechanisms on the xc-mGluR2 network, with potentially synergistic effects on chronic pain and neuro-astrocyte protection. This paper aims to summarise the current evidence on the potential therapeutic role of NAC and ALC, providing an overview of the underlying molecular mechanisms and pathophysiology. It proposes a pathophysiological model explaining the effectiveness of NAC and ALC in treating COVID-19-related neuropsychiatric symptoms.

Keywords: COVID-19; SARS CoV-2; SLC7A11 protein; acetylcarnitine; acetylcysteine; long COVID brain fog; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3.; post-acute COVID-19 syndrome.

Fig. (1)

Potential mechanism of SARS-CoV-2 internalisation. Abbreviations: TfR1: Transferrin Receptor type 1; mGluR2: metabotropic Glutamate 2 receptor; ACE2: angiotensin-converting enzyme 2 receptor; TMPRSS2: type II Transmembrane Serine Proteases; RNA: Sars-Cov-2 virus RNA.

Fig. (2)

Potential pathophysiological mechanisms of SARS-CoV-2 on the CNS. Abbreviations: EAAT: excitatory amino acid transporter; NF-κB: Nuclear Factor-kappa B; NAAG: N-Acetyl-Aspartyl-Glutamate; mGluR3: metabotropic Glutamate 3 receptor; mGluR2: metabotropic Glutamate 2 receptor; Glu: Glutamate; Gln: Glutamine; Cys: Cysteine; System xc^-: cystine/glutamate antiporter system; GCPII: Glutame Carboxypeptidase II; NMDAR: N-methyl-D-aspartate Receptor; TNFα: Tumor Necrosis Factor α.

Fig. (3)

Potential pathophysiological mechanisms and the synergistic effect of NAC and ALC. Abbreviations: NAC: N-Acetyl-Cysteine; ALC: Acetyl-L-Carnitine; ROS: Reactive oxygen species; GSH: Glutathione; EAAT: excitatory amino acid transporter; NF-kB: Nuclear Factor-kappa B; NAAG: N-Acetyl-Aspartyl-Glutamate; mGluR3: metabotropic Glutamate 3 receptor; mGluR2: metabotropic Glutamate 2 receptor; Glu: Glutamate; Gln: Glutamine; Cys: Cysteine; System xc^-: cystine/glutamate antiporter system; Xct subunit (SLC7A11): light-chain subunit of cysteine/glutamate antiporter; GCPII: Glutame Carboxypeptidase II; NMDAR: N-methyl-D-aspartate Receptor; TNFα: Tumor Necrosis Factor α; KAT-II: kynurenin aminotransferase II.