Cadmium (Cd), a highly toxic heavy metal and a substantial environmental pollutant, is found in batteries, cadmium pigments, electroplating, and plastic stabilizers. High concentrations of Cd are normally associated with industrial emission sources such as mining and smelting operations. Other important sources of Cd exposure are linked with the ecosystem (soil or water) or associated with our daily diet [1, 2]. Smoking is also a major source of airborne Cd exposure. Lungs can absorb approximately 5% of the Cd content in each cigarette (50–100 ng). Once Cd enters the body, its effects can last for up to 10 years due to its long half-life [3, 4].
Human beings are at risk of chronic and repetitive exposure to Cd which can consequently be the cause of renal dysfunction, initial tubular damage followed by glomerular damage; cardiovascular and reproductive toxicity [5, 6]; decreased bone mineral density, osteomalacia, diabetes, cancer, and neurotoxicity .
Over the past decades, Cd has been recognized as an important neurotoxic agent. Cd can be the principal cause of cognitive decline, neurodegenerative disorders including Parkinson’s disease or dementia, and even a significant risk factor for depression and mental disorders [8, 9].
When Cd enters the body, it increases the production of free radicals. Increased reactive oxygen species (ROS) generation, oxidative stress, lipid peroxidation, cerebral edema, and cellular dysfunction can all occur and then lead to DNA damage and apoptotic cell death. Cd also interferes with the endothelium reticulum permeability and integrity and stimulates mitogen-activated protein kinase (MAPK)-p38 which once again can lead to cellular death [10–13]. Within the nervous system (both central and peripheral (CNS and PNS)), by disruptions in Na+, K+-ATPase, and calcium (Ca2+) channels functions, Cd can harm neurotransmitter signaling. Monoaminergic, glutaminergic, cholinergic, and GABAergic systems can all be affected, thus deficiencies in motor activity, learning, memory, and possibly emotion may befall [10, 11]. Since humans can be exposed to Cd daily and considering all the severe outcomes as well, the search for a reliable remedy has always been encouraged. Based on published reports, oxidative stress and induced apoptosis are the two most important mechanisms through which Cd can cause toxicity. Rosemary (Rosmarinus officinalis), Ginkgo biloba L., and Black Seed (Nigella Sativa) have shown protective activity against Cd-induced toxicity [14–16].
Minocycline (Mino), is a tetracycline antibiotic that beyond its use in infectious diseases, possesses immunomodulatory effects, suppresses proinflammatory cytokine release, and exerts antiapoptotic properties [17–19]. Owing to its lipophilic structure, Mino can cross the blood-brain barrier and act as a potential neuroprotective agent. Mounting evidence suggests that Mino can decrease the level of caspase-3-cleaved, both inducible and endothelial nitric oxide synthase, and inhibit the MAPK-p38 . Mino's ameliorative effect has been studied in disorders like Parkinson’s disease, Multiple Sclerosis, Huntington’s disease, Alzheimer’s disease, and rheumatoid arthritis. Promising studies have recognized Mino as a preventive candidate for the progression of the aforementioned disorders [19, 21–24]. In animal models, Mino has also shown anti-nociceptive effects in chronic pain including diabetic peripheral neuropathy [25, 26], inflammatory pain [27, 28], and visceral pain .
Regarding the neuroprotective properties of Mino, in the current study, we evaluated the protective effect of Mino against Cd-induced neurotoxicity using the PC12 cell line. Given that Cd causes toxicity mainly through oxidative imbalance and apoptotic cell death, we chose to investigate the anti-oxidant and anti-apoptotic effect of Mino on Cd-induced neurotoxicity.