β-Caryophyllene's potential modulation of the renin-angiotensin system: Implications for anosmia and neuroinflammation in the olfactory circuitry.

The sense of smell perceives odorants via the olfactory circuitry. Sense of smell is essential for multiple species, while its loss in humans (Anosmia) has been described in COVID-19, Parkinson's and Alzheimer's diseases, where neuroinflammation is a common denominator. Olfactory circuitry is proximal to the respiratory tract, therefore, is susceptible to foreign particles intromission that trigger neuroinflammation. The brain Renin-Angiotensin System (RAS) influence neuroinflammation through its counter-regulatory axes: The pro-inflammatory Renin/(Pro)Renin Receptor ((P)RR) axis and the anti-inflammatory Angiotensin-Converting Enzyme 2 (ACE2)/Angiotensin-(1-7) (Ang-(1-7))/Mas Receptor (MasR) axis. Certain phytochemicals with angiotensinergic activity may improve neuroinflammation. Among these, β-Caryophyllene, stands out for its bicyclic sesquiterpenoid structure and its activity toward multiple targets, including the Cannabinoid Receptor 2 and the peripheral ACE2/Ang-(1-7)/MasR axis. It is still unknown whether β-Caryophyllene affects the brain RAS, especially in vulnerable regions to neuroinflammation, like the olfactory circuitry. This study aims to explore the angiotensinergic effect of β-Caryophyllene on anosmia and the neuroinflammation of the olfactory circuitry. Male BALB/c mice were intranasally administered with lipopolysaccharide and orally treated with β-Caryophyllene for seven days. Multiple parameters concerning RAS, olfaction, neuroinflammation, cell death and stress were evaluated. Results demonstrate that β-Caryophyllene improved anosmia, increased ACE2 and Ang-(1-7) levels, reduced pro-inflammatory cytokines as well as reduced corticosterone levels and cell death. Molecular docking showed favorable interactions between β-Caryophyllene and ACE2. Therefore, β-Caryophyllene could be useful against anosmia and neuroinflammation due to the possible regulation of the RAS.