Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins

Abstract

We are living in a terrifying pandemic caused by Sars-CoV-2, in which patients with diabetes mellitus have, from the beginning, been identified as having a high risk of hospitalization and mortality. This viral disease is not limited to the respiratory system, but also affects, among other organs, the central nervous system. Furthermore, we already know that individuals with diabetes mellitus exhibit signs of astrocyte dysfunction and are more likely to develop cognitive deficits and even dementia. It is now being realized that COVID-19 incurs long-term effects and that those infected can develop several neurological and psychiatric manifestations. As this virus seriously compromises cell metabolism by triggering several mechanisms leading to the unfolded protein response (UPR), which involves endoplasmic reticulum Ca²⁺ depletion, we review here the basis involved in this response that are intimately associated with the development of neurodegenerative diseases. The discussion aims to highlight two aspects-the role of calcium-binding proteins and the role of astrocytes, glial cells that integrate energy metabolism with neurotransmission and with neuroinflammation. Among the proteins discussed are calpain, calcineurin, and sorcin. These proteins are emphasized as markers of the UPR and are potential therapeutic targets. Finally, we discuss the role of drugs widely prescribed to patients with diabetes mellitus, such as statins, metformin, and calcium channel blockers. The review assesses potential neuroprotection mechanisms, focusing on the UPR and the restoration of reticular Ca²⁺ homeostasis, based on both clinical and experimental data.

Keywords: COVID-19; UPR; astrocyte; calcium-binding proteins; diabetes mellitus; neuroprotection.

Figure 1

Schematic representation of the UPR in astrocytes. Only PERK and OASIS are represented as ER stress sensor proteins. Upon Ca²⁺ efflux, the chaperone CBPs (e.g., calreticulin) move from the sensor proteins (in the membrane) to the unfolded proteins (in the lumen), promoting the oligomerization of the sensor proteins, and triggering the UPR. In parallel, but not independently, the outgoing Ca²⁺ activates calpain and calcineurin (CaN). CBPs are all represented in red. Note that CaN (independent of enzyme activity) positively modulates PERK. Gene expression in the UPR, in general, is reduced, but some modulating proteins are upregulated, such as sorcin, CHOP, and GFAP, in addition to pro-inflammatory cytokines. Sorcin plays a role at the beginning of the UPR (negatively modulating Ca²⁺ efflux and CHOP expression). CHOP will play an important role in cell death if the triggering factor(s) of the UPR persist. It is important to mention that calpain and CaN modulate ER Ca²⁺-channels and SERCA, but in this scheme, only sorcin, which also plays this role, is highlighted. The image on the right emphasizes the structural relationship and bidirectional communication between the ER and the nucleus, where the main transcription factors of the astroglial inflammatory response (NF-kB, NFAT, and STAT) are highlighted. Abbreviations: CaN, calcineurin; CBP, calcium-binding protein; CHOP, CCAAT-enhancer-binding protein homologous protein; ERAD, ER-associated degradation; GFAP, glial fibrillary acidic protein; NF-kB, nuclear factor kappa B; NFAT, nuclear factor of activated T-cells; OASIS, old astrocyte specifically induced substance; PERK, protein kinase R-like ER kinase PERK; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; STAT, signal transducer and activator of transcription.

Figure 2

Sars-CoV-2-induced UPR in neural cells. The scheme highlights the two pathways of damage to the CNS by the coronavirus, indicating the possible mechanisms triggering UPR. The UPR and the intercellular spread of the UPR (UPR contagion) would be the basis of neurodegenerative diseases.

Figure 3

Modulation of the UPR by drugs prescribed for patients with diabetes mellitus. Metformin inhibits the respiratory chain complex 1 (decreasing ROS) and consequently the efflux of Ca²⁺ from the ER. This could potentially stimulate Ca²⁺ entry via SOCE. Statins down-regulate the expression of CBP chaperones of the ER, calpains, and PERK. Potentially, statins have a dual role, as downregulation of PERK can decrease Ca²⁺ entry into the ER, via SOCE. CCB stimulates STIM-1 and increase the input of Ca²⁺ to the ER. The dashed routes refer to potential pathways and their effects on neural cells, particularly astrocytes, need to be confirmed. Abbreviations: CCB, calcium channel blockers; MAM, mitochondria-associated ER membrane; RC1, respiratory chain complex 1; STIM-1, stromal-interacting molecule 1.