Calcium Channel Blockers: A Possible Potential Therapeutic Strategy for the Treatment of Alzheimer’s Dementia Patients with SARS-CoV-2 Infection

Abstract

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer’s dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aβ) protein, the hallmark of Alzheimer’s dementia. Reversely, deposition of Aβ is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer’s disease (AD) as well as have shown inhibition in various virus infections.

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“…The increase in [Ca 2+ ]i produced by certain viruses through VDCCs has also been demonstrated to be necessary for viral replication, and VDCC blockers have proven to be effective antiviral agents against Japanese encephalitis virus (JEV), ZIKV, DENV, and WNV [23,24,45]. It has been shown that Ca 2+ binds to the fusion protein (FP) of MERS-CoV and the 2 FP domains on the S protein of SARS-CoV during the entry stage of both virus types [27,46,47], nevertheless, this phenomenon still requires further investigation. The use of VDCC blockers has also been associated with lower mortality and decreased risk for intubation in COVID-19 patients; therefore, Ca 2+ could also potentially be involved in the viral entry stage (Figure 2) [48].…”

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“…Although no direct evidence supports that SARS-CoV-2 is related to Ca 2+ regulation, it has been confirmed that Ca 2+ is necessary for viral entry, viral gene replication, and viral particle maturation and release [ 32 ]. The membrane sequence of the fusion peptide of the SARS-CoV-2 glycoprotein depends on Ca 2+ , and Ca 2+ also plays an important role in SARS-CoV-2 virus invasion [ 33 ].…”