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Minocycline for Long COVID


Minocycline is part of the family of tetracycline antibiotics that possess both antibiotic and anti-inflammatory properties. Minocycline has been safely used for more than 40 years which produces beneficial effects in diverse pathophysiological conditions and is emerging as a useful drug in providing neuroprotection as a result of its ability of pass through the blood brain barrier (Garrido-Mesa et al., 2013).

Although the precise mechanism of minocycline actions remain elusive (NO ONE WANTS TO ACCEPT THE CONCEPT OF CHRONIC INFECTION - LEWIS), it appears that effects on multiple enzyme systems and pathways could account for its diverse actions. It inhibits bacterial protein synthesis by preventing aminoacyl-tRNA attachment to the ribosomal acceptor and downregulates the nuclear factor–κ B pathway. In addition, its inhibitory effects on key enzymes like inducible nitric oxide synthase, matrix metalloproteases, phospholipase A2, protein tyrosine nitration, caspases, and other apoptotic molecules, p38 map kinase, poly[ADP] ribose polymerase1 are linked with minocycline's anti-inflammatory, immunomodulatory, and neuroprotective actions (Garrido-Mesa et al., 2013).

Minocycline is a highly lipophilic molecule; this property increases its half-life and allows excellent tissue penetration, and it easily crosses the BBB. Finally, minocycline inhibits HIV activation, proliferation and replication in microglia, macrophages, and lymphocytes (Garrido-Mesa et al., 2013).

We recently found neuroinflammation critical in driving PH and impaired brain-lung-gut communication responsible for PH-associated lung pathology; the number of activated microglia was positively correlated with PH severity (Oliveira et al., 2018; Sharma et al., 2018). This occurred in various PH models such as hypoxia, Sugen-hypoxia, and monocrotaline-induced PH in rats and mice. Moreover, we demonstrated that targeting neuroinflammation by inhibition of microglia activation could be a novel therapeutic strategy for PH.

First, absence of CX3CR1 expression, a condition rendering microglia unable to activate, prevented neuroinflammation and PH induced by hypoxia (Oliveira et al., 2018).

Secondly, minocycline, an anti-inflammatory antibiotic also used as a microglial inhibitor, significantly reduced the numbers and activation of microglia in the paraventricular nucleus of hypothalamus (PVN), reduced expression of cytokines such as IL-1β, IL-6, and TNF-α, attenuated lung inflammation, heart hypertrophy and sympathetic drive in monocrotaline-treated rats (Sharma et al., 2018).

Significant numbers of severely ill COVID-19 patients have diabetes and hypertension, comorbidities where neuroinflammation is an important contributor. Minocycline demonstrated beneficial outcomes in diabetes-linked peripheral and autonomic neuropathy and cognitive impairment in rodents (Syngle et al., 2014; Ismail et al., 2019; Mehta and Banerjee, 2019).

Our study with a small group of diabetic, obese and hypertensive patients, with minocycline used on a compassionate basis, showed consistent weight loss, improved HbA1c, improved neuropathic pain and impressive decrease in blood pressure (Yellowlees Douglas et al., 2012). Data from our ongoing trial (NCT02133885) indicate that minocycline decreases blood pressure, active microglia and plasma pro-inflammatory cells in treatment-resistant hypertensive patients. These observations led us to propose the following hypothesis (Figure 1):

Minocycline attenuates microglia activation and arrests neuro-inflammation resulting in restoration of normal neuronal-microglia communication, controlling the pro-inflammatory profile especially in moderate and severe COVID-19 patients. This decreases the risk of developing long-term CNS consequences of SARS-CoV-2 infection. The following evidence supports our hypothesis:

(i) Minocycline is a safe anti-inflammatory drug;

(ii) In addition to anti-microbial activity, it is anti-inflammatory, antioxidant, inhibits ion channels and apoptosis and promotes neuronal regeneration in rodents (Miyachi et al., 1986; Rifkin et al., 1994; Tikka et al., 2001; Liu et al., 2007; Nutile-McMenemy et al., 2007). These actions, in addition to its ability to inhibit microglia are likely to contribute to beneficial effects in inflammatory diseases and CNS disorders including stroke (O'Dell, 1999; Naderi et al., 2020);

(iii) minocycline has high lipid solubility, readily crossing the BBB;

(iv) minocycline is the leading neuroprotective tetracycline, mainly by inhibition of microglia activation (Garrido-Mesa et al., 2013);

(v) minocycline treatment effectively decreases inflammatory cytokines such as TNF, IL-1β, and IL-6 (Sharma et al., 2018), all highly expressed in COVID-patients and related to increased neurological damage (Chen N. et al., 2020);

(vi) it is not an antiviral, however, it might act directly on the coronavirus by chelating zinc compounds on matrix metalloproteinase necessary for virus survival, infiltration and replication in the host (Sodhi and Etminan, 2020);

(vii) alterations in fecal microbiota in Covid-19 patients were associated with severity and fecal levels of SARS-CoV-2 and gut dysbiosis persisted even after recovery (Zuo et al., 2020). These might also be attenuated by minocycline since it has been shown to modulate the composition of the gut microbiota and attenuate gut pathology in hypertension and depression (Schmidtner et al., 2019; Sharma et al., 2019; Yang et al., 2020);

(viii) Its ability to reduce lung inflammation in PH and potentially beneficial effects in diabetes, obesity and hypertension are added bonuses. Finally, COVID-19 is emerging as a complex disease involving multiple organs and patients undergo multiple drug treatment to control diverse symptoms. Therefore, potential drug interactions should be considered before addition of minocycline since this anti-inflammatory antibiotic could produce adverse interactions with anti-viral drugs, other antibiotics and drugs acting on the central nervous system.

In conclusion, we believe that not only is there is an urgent need for effective therapies to minimize systemic effects of SARS-CoV-2 and its pro-inflammatory profile, but also to mitigate its CNS effects that are potentially long-term. Minocycline has effective mechanisms to protect the CNS, it attenuates neuroinflammation, counteracts the cytokine storm, modulates gut microbiome, and might inhibit viral replication. If confirmed, our hypothesis may represent an important contribution to prevent neurological impacts of infection and improve COVID-19 management.


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