Farnesol quells oxidative stress, reactive gliosis and inflammation during acrylamide-induced neurotoxicity: Behavioral and biochemical evidence
Graphical abstract
Introduction
Industrial activities have increased the chemical intoxication in the general population by introducing an array of new chemicals into the environment and the frequency with which these chemicals are used in everyday lives. A recent study advocated the adverse effects of an array of chemicals associated with day-to-day human life as potent neurotoxins and contributes to neurological disorders (Grandjean and Landrigan, 2014). Acrylamide (ACR) is one such industrial pollutant that is extensively generated during food processing, water treatment, paper packaging and cosmetics manufacturing (Brown et al., 1980, Zhang et al., 2005, Yousef and El-Demerdash, 2006). Human exposure to ACR involves dietary intake of carbohydrates processed at high temperature such as potato crisps and chips, roasted cereals and breads (Tareke et al., 2002). Experimental evidences suggest the relevance of ACR exposure to neurotoxicity, genotoxicity, carcinogenicity and reproductive toxicity in animal models (Shipp et al., 2006). However, available literature strongly correlates neurotoxicity as a primary consequence of ACR exposure in humans (LoPachin and Gavin, 2012, Pennisi et al., 2013). Despite extensive research carried out on ACR-induced neurotoxicity, the exact mechanism still remains obscure.
Oxidative stress represents a critical event in the pathology of chemical-induced neurodegeneration (Selvakumar et al., 2013). Experimental evidences suggest that ACR-induced oxidative stress is characterized by elevated levels of lipid peroxidation (LPO) and protein carbonyl content with a decrease in enzymic and non-enzymic antioxidants (Shinomol et al., 2013). The impairment in redox-homeostasis associated with ACR intoxication is attributed to its adduct formation with glutathione (GSH) and elevated levels of hydrogen peroxide corroborated with increase in reactive oxygen species (ROS) such as hydroperoxide and hydroxyl radicals (Allam et al., 2011, Prasad, 2014).
Although; ACR has been reported to induce oxidative stress that underlies the pathological and neurobehavioral alterations leading to neurodegeneration; effect of ACR intoxication on brain parenchyma in the context of reactive gliosis and associated immunomodulatory events remains obscure. Activated microglia and reactive astrocytes secrete an array of cytotoxic substances such as nitric oxide, hydrogen peroxide, superoxide, pro-inflammatory mediators including interleukin-1β (IL-1β), interleukin-6, tumor necrosis factor-α (TNF-α) and inducible form of nitric oxide synthase (iNOS), promoting recovery by restoring tissue homeostasis (Teismann and Schulz, 2004). Paradoxically, aberrant chronic activation of glial cells is neurotoxic, hastening neuronal demise (Streit et al., 2004).
Evidence suggests that phytochemicals represent a potential candidate for therapeutic intervention of neurodegeneration by directly scavenging and neutralizing free radicals thereby ameliorating oxidative stress-driven inflammatory responses in the brain parenchyma (Prakash et al., 2013). Farnesol a sesquiterpene isolated from the essential oils of ambrette seeds and citronella is a potent anti-oxidant (Jahangir et al., 2006) and exhibits significant anti-inflammatory (Qamar and Sultana, 2008), anti-cancer effects in vivo and in vitro (Joo and Jetten, 2010). We have recently reported that farnesol exerts neuroprotective effects against lipopolysaccharide (LPS)-induced neurodegeneration by regulating intrinsic apoptotic cascade (Santhanasabapathy and Sudhandiran, 2015). However, the effect of farnesol in regulating the activities of brain parenchyma in terms of glial activation remains elusive. Therefore, in this study, we have investigated the neuroprotective efficacy of farnesol against ACR-induced neurotoxicity in terms of behavioral, biochemical and histological aspects, together with status of reactive gliosis and expression of inflammatory cytokines TNF-α, IL-1β, and iNOS in the cortex, hippocampus and striatum of Swiss albino mice.
Section snippets
Drugs and chemicals
ACR and trans-farnesol were purchased from Sigma–Aldrich Co. (St. Louis, MO, USA). The antibodies used in this study were purchased from Santacruz Biotech, USA. Fluoro-Jade C used in this study was a generous gift from Dr. Larry Schumed, National Centre for Toxicological Research, FDA, Jefferson, USA. Ionized calcium-binding adapter molecule-1 (Iba-1) and Glial fibrillary acidic protein (GFAP) antibody were generously gifted by Dr. Pankaj Seth, National Brain Research Institute, Gurgaon,
Farnesol improves neuromuscular strength and motor coordination
Fig. 1 represents gait performances of the control and the experimental groups of animals. Control animals displayed consistent forelimb–hindlimb coordination with regular overlapping patterns (A). ACR-induced animals exhibited weaving footprint patterns characterized by altered front/hind paw overlapping patterns with altered sway, stance and stride lengths (B). Farnesol-treated mice exhibited regular overlapping pattern with slight alterations in the stance lengths (C). No significant
Discussion
Animal models involving toxicity-associated pathologies serve as morphological templates for neurodegeneration and help to gain insights into cellular and molecular mechanisms of cell death (Dajas-Bailador et al., 2000, Abou-Donia et al., 2003, Yin et al., 2007). Early research involving experimental animals shows that ACR-induced morphological and neurobehavioral changes recapitulate symptoms of human intoxication (Spencer and Schaumburg, 1974, Tilson, 1980, Lopachin and Lehning, 1993).
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
The authors thank CSIR-UGC, New Delhi, India for financial assistance in the form of Junior Research Fellowship (2011–2013) and Senior Research Fellowship (from 2013 onward) awarded to RSS (F.17-42/08(SA-1).
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2022, Clinical ImmunologyCitation Excerpt :FOL also has potent anti-oxidant and anti-inflammatory effects in vitro [25,26]. Neuroprotection by FOL was demonstrated in a murine model of neurodegeneration (LPS-induced) and a model of neurotoxicity (acrylamide-induced) in a mechanism based on the regulation of the production of free radicals by glial cells and pro-inflammatory cytokine production in the CNS [27,28]. In these studies, FOL was administered intraperitoneally (i.p.) at a daily dose of 100 mg/kg without evidence of toxicity while improving gait performance, neuromuscular function, and fine motor coordination.