1 Percentage of the compound calculated by comparing the gas chromatographic peak area of the analyte with the total area of all detected peaks.
a Depending upon different species.
b Depending upon different cultivars.
c Depending upon sub-species.
3. β-Caryophyllene: Alteration of Oxidative Stress and Mitochondrial Dysfunction
A number of studies have suggested the alteration of oxidative stress and mitochondrial dysfunction by
β-caryophyllene and
β-caryophyllene-containing vegetable extracts, as one of the potential mechanisms in protecting neurons from degeneration
[28]. Chávez-Hurtado et al. (2020) observed a reduction in DNA oxidation and overexpression of glial fibrillary acidic proteins with
β-caryophyllene (10 mg/kg, p.o. for 4 weeks) in the prefrontal cortex and hippocampus of BALB/c mice withd-galactose induced aging
[29]. In an in vivo model of PD,
β-caryophyllene (50 mg/kg, i.p. for 4 weeks) ameliorated oxidative stress (restored antioxidant enzymes, increased GSH, and inhibited lipid peroxidation), neuroinflammation (decreased levels of IL-1
β, IL-6, and TNF-α, and downregulated COX-2 and iNOS expression), and glial activation as well as rescuing dopaminergic neurons
[30].
Javed et al. investigated the CB2 receptor mediated neuroprotective effects of
β-caryophyllene in a rotenone induced animal model of PD
[31]. Rotenone (2.5 mg/kg) induced a significant loss in dopaminergic neurons in the substantia nigra pars compacta and dopaminergic striatal fibers, following the activation of astrocytes and microglia when injected peritoneally once daily for 4 weeks. Moreover, rotenone downregulated antioxidant enzymes, increased nitrite levels and induced proinflammatory cytokines (IL-1
β, IL-6 and TNF-α) and inflammatory mediators (NF-κB, COX-2, and iNOS). Supplementation with
β-caryophyllene (50 mg/kg once daily for 4 weeks, 30 min prior to rotenone administration) attenuated the induction of pro-inflammatory cytokines and inflammatory mediators, prevented the depletion of glutathione, reduced lipid peroxidation, and augmented antioxidant enzymes (SOD and CAT). Tyrosine hydroxylase immunohistochemistry showed the rescue of dopaminergic neurons and fibers following decreased activation of glial cells.
β-caryophyllene protected C6 glioma cells from glutamate induced cytotoxicity through alteration of antioxidant responses, mainly by inhibition of ROS production and restoration of MMP via CB2 receptor dependent nuclear factor erythroid 2–related factor 2 (Nrf2) activation
[32]. In a neurovascular unit model of oxygen-glucose deprivation and re-oxygenation—induced injury,
β-caryophyllene significantly decreased blood–brain barrier (BBB) permeability, reduced neuronal apoptosis, relieved oxidative stress damage, decreased secretion of inflammatory cytokines, downregulated metalloproteinase-9 expression/activity and Bcl-2-associated X protein (Bax) expression, and upregulated expression of claudin-5, occludin, zonula occludens-1 (ZO-1), growth-associated protein-43 (GAP-43) and B-cell lymphoma 2 (Bcl-2)
[33]. Conversely,
β-caryophyllene relieved seizures in mice induced by pentylenetetrazole, but anti-convulsant doses (0, 10, 30, and 100 mg/kg i.p.) showed no benefits over pentylenetetrazole related oxidative stress i.e., thiobarbituric acid-reactive substances and nonprotein thiol content
[34].
Lou et al. (2016) found an attenuation of focal cerebral ischemia-reperfusion injury in rats by treatment with
β-caryophyllene through enhanced expression of Nrf2 and HO-1, and restored activity and expression of antioxidant enzymes, i.e., superoxide dismutase (SOD) and catalase (CAT)
[35]. In C57BL/6 mice,
β-caryophyllene ameliorated the development of experimental autoimmune encephalomyelitis through inhibiting the production of hydrogen peroxide (H2O2), IFN-γ, TNF-α, IL-17 and NO, and decreasing the number of inflammatory infiltrates and neurological damage
[36]. An in vitro study demonstrated the alleviation of 1-methyl-4-phenylpyridinium induced neurotoxicity by
β-caryophyllene through restoring MMP and increasing intracellular activity of GSH and glutathione peroxidase (GPx), where antioxidant effects were found to be CB2 receptor dependent
[37]. Apoptosis was prevented in same study by inhibition of the up-regulation of caspase-3 and Bax, restoring Bcl-2 expression, and suppressing heme oxygenase-1 (HO-1) activation and c-Jun
N-terminal kinase (JNK) phosphorylation.
Pinus halepensis Mill. essential oil attenuated Alzheimer’s toxic A
β (1-42)-induced memory impairment and oxidative stress in rat hippocampus
[38]. Inhalation of
P. halepensis essential oil (1 and 3%) for 21 days resulted in the inhibition of hippocampal AChE activity, elevation of hippocampal antioxidant markers (SOD, CAT, GPx and GSH), and attenuation of A
β-induced elevation of malondialdehyde (MDA) levels. Phytochemical screening of essential oils revealed the presence of 45 different compounds, with 33 of those compounds having been identified and quantified. Sesquiterpenes (
β-caryophyllene) and monoterpenes (α-pinene, myrcene, terpinolene, and 2-phenylethylisovalerate) were the most abundant compounds present in the essential oil, while diterpenes (mainly cembrene) represent only 2.50% of the phytochemicals present. More importantly,
β-caryophyllene was found to be the most abundant compound present with the highest percentage of 29.45%.
Essential oils extracted from the dried leaves of
Aloysia citrodora Palau displayed significant antioxidant and protective effects against both H
2O
2 and A
β-induced neurotoxicity in CAD neuroblastoma cell lines
[39]. H
2O
2 (250 μM) and A
β (10 μM) failed to elicit neurotoxic responses in the presence of
A. citrodora essential oil (0.01 and 0.001 mg/mL). The in vitro antioxidant effects of
A. citrodora essential oil was confirmed by its Fe
2+ chelating capacity. The major chemical components detected in this essential oil were limonene, geranial, neral, 1, 8-cineole, curcumene, spathulenol and caryophyllene oxide.
The clove oil obtained from
Syzygium aromaticum (L.) Merr. and L.M. Perry is known to contain eugenol as its most abundant compound (87.34%), with eugenol acetate (5.18%) and
β-caryophyllene (2.01%) being present in smaller amounts
[40]. Kumar et al. reported the neuroprotective potential of clove oil in intra-cerebroventricular (ICV) colchicine-induced memory impairment in rats
[41]. Treatment of colchicine challenged rats with
S. aromaticum (0.05 mL/kg and 0.1 mL/kg, i.p.) significantly improved cognitive dysfunction, with a marked reduction of AChE activity, lipid peroxidation levels, and nitrite concentrations, and restoration of GSH and mitochondrial respiratory enzyme complex (I–IV) activities. Authors linked the attenuation of cognitive dysfunction with antioxidant and mitochondrial restoring mechanisms.
Hyptis fruticosa Salzm. ex Benth (also known as
Eplingiella fruticosa) leaf essential oil (containing
β-caryophyllene, bicyclogermacrene and 1,8-cineole), complexed with
β-cyclodextrin, showed neuroprotective effects in a mouse model of PD by decreasing membrane lipid peroxide levels in the striatum and preserving dopaminergic depletion in the striatum and substantia nigra pars compacta, when administered at a dose of 5 mg/kg, p.o. for 40 days
[42].
Ocimum basilicum L. essential oil attenuated ethidium bromide-induced cognitive deficits as well as neuroinflammation, astrogliosis and mitochondrial dysfunction in the prefrontal cortex of rats, with induced MS like manifestations
[43].
O. basilicum (100 and 200 μL/kg) significantly mitigated ethidium bromide-induced neuroinflammation by increasing the levels of proinflammatory cytokines (TNF-α and IL-6) and astrogliosis by increasing (Glial fibrillary acidic protein (GFAP) and Ionized calcium binding adaptor molecule-1 (Iba-1) levels. In addition, mitochondrial function, integrity, respiratory control rate, ATP production, and mitochondria-dependent apoptosis were positively regulated in the prefrontal cortex of rats by treatment with
O. basilicum. Chemical analysis of the essential oil derived from
O. basilicum L. demonstrated the presences of several phytoconstituents, with methyl chavicol, geranial, neral and caryophyllene oxide being major components
[44].
Salvia rosmarinus Spenn. essential oil (comprised chemically of 1,8-cineole, α-pinene, camphor, and trans-caryophyllene) exhibited strong antioxidant effects evaluated by DPPH, ABTS, FRAP and
β-carotene bleaching tests and confirmed by the relative antioxidant capacity index and significant acetylcholinesterase (AChE) inhibitory activities, suggesting neuroprotective potential in patients with AD
[45].