Protective antioxidative and anti-inflammatory actions of β-caryophyllene against sulfasalazine-induced nephrotoxicity in rat

Abstract

The pathogenesis of sulfasalazine (SFZ)-induced nephrotoxicity is unclear. Moreover, there are no reports on the protective effects of β-caryophyllene (BCP) against SFZ-induced renal injury. Hence, in this study, we measured several oxidative stress and inflammatory regulatory molecules alongside the effects of BCP in SFZ-intoxicated rats. Male rats ( n = 48) were distributed to six equal groups as follows: negative control (NC), normal rats treated with low (N-LD; 200 mg/kg/day) and high (N-HD; 400 mg/kg/day) BCP doses, and animals treated with SFZ individually (PC; 600 mg/kg/day) or combined with BCP low (P-LD) and high (P-HD) doses. All drugs were administrated for 14 consecutive days. The NC, N-LD, and N-HD groups showed comparable renal histology and biochemistry. In contrast, abnormal histology, and increased creatinine and urea alongside oliguria and proteinuria were detected in the PC group. Renal specimens from the PC group revealed increased levels of nuclear factor-kappa B (NF-κB), transforming growth factor (TGF)-β with kidney injury molecule (KIM)-1, while the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) declined, relative to controls. The PC renal tissue also had markedly higher levels of inflammatory cytokines (tumor necrosis factor [TNF]-α/interleukin [IL]-1β/IL-6) and pro-oxidants (malondialdehyde [MDA]/H2O2/protein carbonyls), whereas those of antioxidants (glutathione [GSH]/glutathione peroxidase [GPx]/superoxide dismutase-1 [SOD1]/catalase [CAT]) and IL-10 decreased and were associated with marked apoptosis. Both BCP regimens ameliorated renal functions and histology, and reduced NF-κB, TGF-β, and KIM-1 levels in addition to those of oxidative stress and inflammation markers. Both protocols also augmented Nrf2, AMPK, AKT, antioxidants, and IL-10. However, P-HD showed better alleviating effects than the N-HD group. In conclusion, this study is the first to link NF-κB, TGF-β, Nrf2, AMPK, and AKT with SFZ-induced nephrotoxicity. In addition, this is the first report to reveal antioxidative and anti-inflammatory effects for BCP against SFZ-associated nephropathy.

β-Caryophyllene Ameliorates Cyclophosphamide Induced Cardiac Injury: The Association of TLR4/NFκB and Nrf2/HO1/NQO1 Pathways

“…In the present study, treatment with BCP resulted in lipid peroxidation mitigation as well as dose-dependent enriched antioxidant capacity, as revealed by lowered MDA and H 2 O 2 and enhanced GPx, SOD, CAT, and GRx activities. These results agree with the previously reported antioxidant capacity of BCP in myocardium [ 16 , 18 ], hepatic [ 48 ], and renal [ 49 ] tissues. Furthermore, treatment with BCP was related with a significant escalation in nuclear translocation of Nrf2, with subsequent HO1 and NQO1 amplification, indicating an intensified Nrf2/HO1/NQO1 signaling pathway.…”

“…Previously, Li et al [ 50 ] reported that BCP enhanced Nrf2 activation in high glucose (HG)-induced glomerular mesangial cells (MCs). Additionally, via activating the Nrf2/HO1 signaling pathway, BCP mitigated focal cerebral ischemia-reperfusion damage [ 20 ], MPTP induced Parkinson’s disease [ 51 ], aflatoxin B1 induced liver toxicity [ 48 ], and sulfasalazine-induced nephrotoxicity [ 49 ].…”

“…In the current study, management with BCP was associated with lowered levels of TLR4, NFκB, TNF-α, IL-1β, and IL-6, indicating limited inflammation because of the anti-inflammatory effect of BCP. A wide range of studies documented the anti-inflammatory activity of BCP in different models, e.g., in arthritic [ 11 ], skin wound excision [ 9 ], sulfasalazine induced nephrotoxicity [ 49 ], Mycoplasmal pneumonia [ 52 ], and others. BCP depressed caspase-3, caspase-9, and Bax and increased Bcl2 levels, indicating lessened apoptosis state with the myocardium tissue.…”

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

“…Therefore, due to its pleiotropic properties (including anti-diabetic, antitumoral, and anti-allodynic activities), the CB 2 R-mediated therapeutic potential of BCP in the neuroprotection, cardioprotection, hepatoprotection, nephroprotection, and gastroprotection have been demonstrated in many studies [ 47 , 48 , 87 , 98 , 99 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 ].…”

“…BCP–CB 2 R interactions trigger several intracellular signallings, including cAMP inhibition, intracellular calcium release, stimulation of SIRT-1/PGC-1α (sirtuin 1/peroxisome proliferator-activated receptor γ coactivator-1α), and AMPK (AMP-activated protein kinase) pathways, as well as mitogen-activated kinase (MAPK) activation [ 42 , 119 , 127 , 128 , 129 ]. Notably, MAPKs can modulate PPAR activity through direct phosphorylation [ 130 ].…”