The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 ( ACE2 ) and transmembrane protease/serine subfamily member 2 ( TMPRSS2 ) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2 , and thus ACE2 -mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4 + and CD8 + T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.

It is aimed to investigate the central antinociceptive effect of protocatechuic acid and the involvement of stimulation of opioidergic, serotonin 5-HT, α2-adrenergic and muscarinic receptors in protocatechuic acid-induced central analgesia in mice. Time-dependent antinociceptive effects of protocatechuic acid at the oral doses of 75, 150 and 300 mg/kg were tested in hot-plate (integrated supraspinal response) and tail-immersion (spinal reflex) tests in mice. To investigate the mechanisms of action; the mice administered 300 mg/kg protocatechuic acid (p.o.) were pre-treated with non-specific opioid antagonist naloxone (5 mg/kg, i.p.), serotonin 5-HT receptor antagonist ketanserin (1 mg/kg, i.p.), α2-adrenoceptor antagonist yohimbine (1 mg/kg, i.p.) and non-specific muscarinic antagonist atropine (5 mg/kg, i.p.), respectively. The antinociceptive effect of protocatechuic acid was observed at the doses of 75, 150 and 300 mg/kg in tail-immersion test, at the doses of 150 and 300 mg/kg in hot-plate test at different time interval. The enhancement in the latency of protocatechuic acid-induced response to thermal stimuli was antagonized by yohimbine, naloxone and atropine in tail-immersion test, while it was antagonized only by yohimbine and naloxone pretreatments in hot-plate test. These results indicated that protocatechuic acid has the central antinociceptive action that is probably organized by spinal mediated cholinergic and opiodiergic, also spinal and supraspinal mediated noradrenergic modulation. However, further studies are required to understand how protocatechuic acid organizes the interactions of these modulatory systems. As a whole, these findings reinforce that protocatechuic acid is a potential agent that might be used for pain relief. Additionally, the clarification of the effect and mechanisms of action of protocatechuic acid will contribute to new therapeutic approaches and provide guidance for new drug development studies.

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