Abstract
Methylphenidate (MPH) abuse causes adverse neurobehavioral and neurochemical effects. Some herbal components such as crocin have shown neuroprotective properties. The current study evaluates the potential role of the cyclic AMP response element binding protein (CREB)‑brain‑derived neurotrophic factor (BDNF) signaling pathway in mediating the neuroprotective effects of crocin against MPH‑induced neurotoxicity in rats. Seventy adult male rats were randomly divided into seven groups. Group 1 and 2 received 0.7 ml/rat of normal saline and 10 mg/kg of MPH, respectively. Groups 3, 4, 5, and 6 were treated simultaneously with MPH (10 mg/kg) and crocin (10, 20, 40, and 80 mg/kg, respectively) for 21 days. Group 7 was treated with crocin (80 mg/kg) alone for 21 days. The Morris water maze (MWM) and open field test were used to assess cognitive and locomotor activities. Hippocampal neurotoxicity parameters and levels of BDNF and CREB were evaluated. Simultaneous treatment with various doses of crocin reduced the MPH‑induced cognition disturbances and hyperlocomotion. In addition, lipid peroxidation increased with MPH treatment and levels of the oxidized forms of glutathione (GSSG), interleukin 1 beta (IL‑1β), tumor necrosis factor alpha (TNF‑α), and Bax increased. MPH treatment decreased levels of the reduced form of glutathione (GSH), P‑CREB, Bcl‑2, and BDNF in the hippocampus. MPH also reduced activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase in the hippocampus. In contrast, crocin attenuated MPH‑induced oxidative stress, inflammation, and apoptosis, and increased levels of P‑CREB and BDNF. Thus, crocin - likely via stimulation of the P‑CREB/BDNF signaling pathway - displayed neuroprotection against MPH‑induced neurotoxicity.
Highlights
Abuse of methylphenidate (MPH), a neurostimu‐ lating agent, has increased in recent years (Martins et al, 2006)
MPH has different effects on the GABAergic system during chronic and acute treatment; previous studies have demonstrated that chronic MPH‐induced locomotion and repetitive movements were due to a decrease in GABA transmis‐ sion, whereas the GABAergic system was not signifi‐ cantly altered following acute MPH treatment (Freese et al, 2012; Goitia et al, 2013)
In the group treated with crocin alone the percent‐ age of time that the animals spent in the target quarter in the Morris water maze (MWM) did not change significantly when com‐ pared to the control group (Fig. 1D)
Summary
Abuse of methylphenidate (MPH), a neurostimu‐ lating agent, has increased in recent years (Martins et al, 2006). Previous studies have demonstrated that low doses and acute treatment of MPH can activate the glutamate re‐ ceptor, whereas high doses and chronic treatment of MPH can inhibit the glutamate receptor and this inhi‐ bition is responsible for the adverse cognitive effects (Cheng et al, 2014a; 2014b). Experimental studies have confirmed the potential effects of MPH on neuro‐ degeneration of several brain areas including the hip‐ pocampus, which is involved in cognition and anxiety (Andreazza et al, 2007; Jones and Dafny, 2013). Previous studies have demonstrated that MPH abuse can lead to the production of apoptotic proteins, such as Bax, caspase‐3, 8, and 9, which can result in DNA fragmentation in various brain regions including the hippocampus and amygdala (Martins et al, 2006; Andreazza et al, 2007). MPH‐induced neurotoxicity seems to be more apparent in certain brain areas, the hippocampus (including CA1, CA2, CA3, and DG subregions) and the amygdala (Morton and Stockton, 2000; Motaghinejad et al, 2017a)
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