Hydrogen Sulfide Protects Hippocampal Neurons Against Methamphetamine Neurotoxicity Via Inhibition of Apoptosis and Neuroinflammation Fateme Ghanbari 1 & Mehdi Khaksari 2 & Golamhassan Vaezi 1 & Vida Hojati 1 & Abdolhossein Shiravi 1 Received: 6 August 2018 /Accepted: 11 November 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Methamphetamine (METH) known as a highly neurotoxic compound associated with irreversible brain cell damage that results in neurological and psychiatric abnormalities. The mechanisms of METH intoxication mainly involve intraneuronal events including oxidative stress, excitotoxicity, and dopamine oxidation. Based on recent studies, H 2 S can protect neurons through anti-inflammatory, antioxidant, and antiapoptotic mechanisms. Therefore, we aimed to study the effects of protection of H 2 S against METH neurotoxicity. The 72 male Wistar rats were randomly allocated into six groups: control (n, 12), H 2 S(n, 12), METH (n, 12), METH + H 2 S 1 mg/kg (n, 12), METH + H 2 S 5 mg/kg (n, 12), and METH + H 2 S 10 mg/kg (n, 12) groups, (NaHS as a H 2 S donor; 1, 5, 10 mg/kg). METH neurotoxicity was induced by 40 mg/kg of METH in four intraperitoneal (IP) injections (e.g., 4 × 10 mg/kg q. 2 h, IP). NaHS was administered at 30 min, 24 h, and 48 h after the final injection of METH. Seven days after METH injection, the brains were removed for biochemical assessments, glial fibrillary acidic protein (GFAP), and caspase-3 immunohistochemistry staining. H 2 S treatment could significantly increase both superoxide dismutase and glutathione (P < 0.01), and a reduction was observed in malondialdehyde (P < 0.05) and TNF-α (P < 0.01) versus the METH group. Moreover, H 2 S could significantly decrease caspase-3 and GFAP-positive cells in the CA1 region of the hippocampus (P < 0.01) compared to the METH group. According to the findings, H 2 S makes significant neuroprotective impacts on METH neurotoxicity due to its antioxidant and anti-inflammatory activities. Keywords Hydrogen sulfide . Methamphetamine neurotoxicity . Apoptosis . Neuroinflammation . Antioxidant activity Introduction Methamphetamine (METH) is recognized as a highly addic- tive psycho-stimulant, influencing the monoamine neuro- transmitter system of the brain that leads to euphoria and in- creased energy and alertness (Yu et al. 2015). METH-induced neurotoxicity seems to have a partly similar pathogenesis to other neurodegenerative disorders, such as Parkinson’ s and Alzheimer’ s diseases (Gonçalves et al. 2008). Although the exact mechanism of METH-induced neurotoxicity remains unknown, some important factors have been introduced as contributing mechanisms and have been noted in different hypotheses including oxidative stress (Pereira et al. 2006), dopamine oxidation, and excitotoxicity, as well as glutamate-mediated neurotoxicity (Cadet et al. 2007) (Thomas et al. 2004). METH enters into the terminal or neuron via dopamine (DA) or 5-hydroxytryptamine (5-HT) transporters. Monoamine oxidases (MAO) and auto-oxidation result in the oxidation of displaced amines to reactive oxygen species (ROS) (Cubells et al. 1994), associated with further produc- tion of ROS (through H 2 O and NO) (Bowyer et al. 1995) and necrotic cell death. According to previous studies, METH diffuses in cell membranes, such as intracellular organelles, e.g., mitochondria (Davidson et al. 2001). METH may be capable of destroying neurons through direct free radical for- mation and stimulation of apoptotic cascades depends on mi- tochondria (Seiden and Sabol 1996). Malondialdehyde (MDA), which is a cytotoxic lipid peroxidation product, is recognized as an oxidative stress biomarker, indicating the * Mehdi Khaksari Khaksari417@yahoo.com 1 Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran 2 Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran Journal of Molecular Neuroscience https://doi.org/10.1007/s12031-018-1218-8