Limonene, a Monoterpene, Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Modulating Neuroinflammation, Hippo Signaling and Apoptosis in Rats

Abstract

Rotenone (ROT) is a naturally derived pesticide and a well-known environmental neurotoxin associated with induction of Parkinson’s disease (PD). Limonene (LMN), a naturally occurring monoterpene, is found ubiquitously in citrus fruits and peels. There is enormous interest in finding novel therapeutic agents that can cure or halt the progressive degeneration in PD; therefore, the main aim of this study is to investigate the potential neuroprotective effects of LMN employing a rodent model of PD measuring parameters of oxidative stress, neuro-inflammation, and apoptosis to elucidate the underlying mechanisms. PD in experimental rats was induced by intraperitoneal injection of ROT (2.5 mg/kg) five days a week for a total of 28 days. The rats were treated with LMN (50 mg/kg, orally) along with intraperitoneal injection of ROT (2.5 mg/kg) for the same duration as in ROT-administered rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers following activation of glial cells (astrocytes and microglia). ROT treatment enhanced oxidative stress, altered NF-κB/MAPK signaling and motor dysfunction, and enhanced the levels/expressions of inflammatory mediators and proinflammatory cytokines in the brain. There was a concomitant mitochondrial dysfunction followed by the activation of the Hippo signaling and intrinsic pathway of apoptosis as well as altered mTOR signaling in the brain of ROT-injected rats. Oral treatment with LMN corrected the majority of the biochemical, pathological, and molecular parameters altered following ROT injections. Our study findings demonstrate the efficacy of LMN in providing protection against ROT-induced neurodegeneration.

7-ketocholesterol enhances BACE1-amyloid precursor protein cleavage and amyloidogenic peptide generation targeted by natural molecules

“…Noticeably, there was a considered decrease in the level of lipid and protein oxidation which was regulated by bornyl acetate and menthol treatment. On the other hand, natural sources of antioxidants are used to enhance the normal mechanism, hence the bio-active agents with one such effective derivative monoterpene has been reported to scavenge the free radical thus reducing the oxidation of other cellular molecules [113,114]. Citronellol enhanced anti-oxidant enzymes against rotenone induced neuronal damage reduced the level of lipid peroxidation [115], reduction in advanced glycation end products were reported by 1,8-cineole [116] and dihydroactinidiolide signi cantly reduced lipid peroxidation and protein carbonylation in SH-SY5Y cells induced by sodium dithionite, glutamate, amyloid β and colchicine [117].…”

Therapeutic Potential of Myrtenal and Its Derivatives—A Review

“…Derivatives of diol 1, compounds 3 and 4, showed neuroprotective effects in vitro and in several experimental mice models (MPTP-, rotenone-, and haloperidol-induced) of Parkinson's disease [66,67] (Figure 2). Neuroprotective potential was demonstrated also for carvacrol [68][69][70], limonene [71][72][73], geraniol [74,75], citronellol [76], carveol [77], 1,8-cineole [78], paeoniflorin [79], α-pinene [80], and linalool [81].…”

“…Derivatives of diol 1, compounds 3 and 4, showed neuroprotective effects in vitro and in several experimental mice models (MPTP-, rotenone-, and haloperidol-induced) of Parkinson's disease [66,67] (Figure 2). Neuroprotective potential was demonstrated also for carvacrol [68][69][70], limonene [71][72][73], geraniol [74,75], citronellol [76], carveol [77], 1,8-cineole [78], paeoniflorin [79], α-pinene [80], and linalool [81]. Guzmán-Gutiérrez et al (2012) reported an antidepressant effect of β-pinene and linalool [82], and Deng et al (2015) found that thymol demonstrated this property in a model of chronic mild stress in mice [83].…”

The Pharmacological Effects and Potential Applications of Limonene From Citrus Plants: A Review

“…Also, limonene inhibited acetylcholinesterase with an IC50 close to that of galantamine. 75 Eddin et al 76 found that limonene can protect rats from rotenone-induced dopaminergic neurodegeneration via regulating apoptosis, neuroinflammation, and hippo signaling.…”