Effects of acute doses of methylphenidate on inflammation and oxidative stress in isolated hippocampus and cerebral cortex of adult rats.

Methylphenidate (MPH) is a stimulatory agent in brain with unknown long-term consequences. In this study, MPH-induced neurodegeneration in adult rat brain was assessed. Rats were acutely treated with different doses of MPH. Open Field Test was used to investigate anxiety and depression levels. Inflammatory factors and anti-oxidant activity were also evaluated in isolated hippocampus and cerebral cortex. MPH treated groups (10 and 20 mg/kg) demonstrated anxiety and depression like behavior in OFT. MPH significantly increased lipid peroxidation, GSSG level, IL-1ß and TNF-α in isolated tissues. In addition, MPH at the same doses (10 and 20 mg/kg) reduced GSH, superoxide dismutase, glutathione peroxidase and glutathione reductase activity significantly in hippocampus and cerebral cortex. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats.

Possible involvements of glutamate and adrenergic receptors on acute toxicity of methylphenidate in isolated hippocampus and cerebral cortex of adult rats.

Neurodegeneration induced by methylphenidate (MPH), as a central stimulant with unknown long-term consequences, in adult rats' brain and the possible mechanisms involved were studied. Rats were acutely treated with MPH in the presence and absence of some receptor antagonists such as ketamine, topiramate, yohimbine, and haloperidol. Motor activity and anxiety level in rats were monitored. Antioxidant and inflammatory parameters were also measured in isolated hippocampus and cerebral cortex. MPH-treated groups (10 and 20 mg/kg) demonstrated anxiety-like behavior and increased motor activity. MPH significantly increased lipid peroxidation, GSSG content, IL-1ß and TNF-α levels in isolated tissues, and also significantly reduced GSH content, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in hippocampus and cerebral cortex. Pretreatment of animals by receptor antagonists caused inhibition of MPH-induced motor activity disturbances and anxiety-like behavior. Pretreatment of animals by ketamine, topiramate, and yohimbine inhibited the MPH-induced oxidative stress and inflammation; it significantly decreased lipid peroxidation, GSSG level, IL-1ß and TNF-α levels and increased GSH content, SOD, GPx, and GR activities in hippocampus and cerebral cortex of acutely MPH-treated rats. Pretreatment with haloperidol did not cause any change in MPH-induced oxidative stress and inflammation. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats and these changes might probably be mediated by glutamate (NMDA or AMPA) and/or α2 -adrenergic receptors.

Neuroprotective effects of various doses of topiramate against methylphenidate induced oxidative stress and inflammation in rat isolated hippocampus.

Methylphenidate (MPH) abuse causes neurodegeneration. The neuroprotective effects of topiramate (TPM) have been reported but its putative mechanism remains unclear. The current study evaluates the role of various doses of TPM on protection of rat hippocampal cells from MPH-induced oxidative stress and inflammation in vivo. Seventy adult male rats were divided into six groups. Group 1 received normal saline (0.7 mL/rat) and group 2 was injected with MPH (10 mg/kg) for 21 days. Groups 3, 4, 5, 6 and 7 concurrently were treated by MPH (10 mg/kg) and TPM (10, 30, 50, 70 and 100 mg/kg, intraperitoneally (i.p.)), respectively for 21 days. After drug administration, the open field test (OFT) was used to investigate motor activity. Oxidative, antioxidant and inflammatory factors were measured in isolated hippocampus. Also, the brain-derived neurotrophic factor (BDNF) level was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. Cresyl violet staining of Dentate Gyrus (DG) and CA1 cell layers of the hippocampus were also performed. MPH significantly disturbs motor activity in OFT and TPM (70 and 100 mg/kg) decreased this disturbance. Also MPH significantly increased lipid peroxidation, mitochondrial reduced state of glutathione (GSH) level, interleukin (IL)-1ß and tumour necrosis factor (TNF)-α and BDNF level in isolated hippocampal cells. Also superoxide dismutase, glutathione peroxidase and glutathione reductase activity significantly decreased. Various doses of TPM attenuated these effects and significantly decreased MPH-induced oxidative damage, inflammation and hippocampal cell loss and increased BDNF level. This study suggests that TPM has the potential to be used as a neuroprotective agent against oxidative stress and neuroinflammation induced by frequent use of MPH.

Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats.

Methylphenidate (MPH) is a central stimulant, prescribed for the treatment of attention deficit/hyperactivity disorder. The long-term behavioral consequences of MPH treatment are unknown. In this study, the oxidative stress and neuroinflammation induced by various doses of MPH were investigated. Forty adult male rats were divided into 5 groups; and treated with different doses of MPH for 21 days. Twenty four hours after drug treatment, Open Field Test (OFT) was performed in all animals. At the end of the study, blood cortisol level (BCL) was measured and hippocampus was isolated and oxidative stress and inflammation parameters and histological changes were analyzed. Chronic MPH at all doses decreased central square entries, number of rearing, ambulation distance and time spent in central square in OFT. BCL increased in doses 10 and 20mg/kg of MPH. Furthermore, MPH in all doses markedly increased lipid peroxidation, mitochondrial oxidized glutathione (GSSG) level, Interleukin 1ß (IL-1ß) and Tumor Necrosis Factor α (TNF-α) in isolated hippocampus. MPH (10 and 20mg/kg) treated groups had decreased mitochondrial reduced glutathione (GSH) content, and reduced superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRx) activities. 10 and 20mg/kg of MPH change cell density and morphology of cells in Dentate Gyrus (DG) and CA1 areas of hippocampus. Chronic treatment with high doses of MPH can cause oxidative stress, neuroinflammation and neurodegeneration in hippocampus of adult rats.

The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats.

Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine-induced dependency, oxidative stress, and apoptosis. Forty-eight male rats were randomly divided into six groups. Rats in groups 1-5 were made morphine dependent by an increasing manner of morphine for 7 days (15-45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase-3, caspase-9, TNF-α, and IL-1ß and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl-2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine-induced dependency and neurodegeneration.

Protective effects of various dosage of Curcumin against morphine induced apoptosis and oxidative stress in rat isolated hippocampus.

BACKGROUND: During recent years, the defensive role of Curcumin against oxidative stress and apoptosis has been experimentally documented. Long term consumption of morphine induces apoptosis and oxidative stress which may cause serious damage to brain cells. To investigate whether Curcumin could protect rat's hippocampus against morphine induced destruction, we assessed isolated hippocampus cells for oxidative stress, anti oxidant factor and apoptotic factor activities. METHODS: For this, 40 adult male rats were taken and randomly allocated to one of the five groups. Groups 1 and 2 received morphine (45 mg/kg) and normal saline (0.2 ml/rat) respectively for four weeks. Groups 3, 4 and 5 concurrently were treated with morphine (45 mg/kg, sc) and Curcumin (10, 20 and 40 mg/kg) for four weeks. RESULTS: The results showed that morphine significantly increased lipid peroxidation, mitochondrial GSH level, concentration of Bax; caspase-3 and caspase-9 activities while decreasing Bcl-2 concentration. Further, a significant decrease in superoxide dismutase and glutathione peroxidase activity was also observed. Various dosage of Curcumin attenuated these effects by significantly lowering lipid peroxidation, GSSG level, Bax concentration, caspase-3 and caspase-9 activities, while increasing superoxide dismutase and glutathione peroxidase activity, GSH level and Bcl-2 concentration. CONCLUSIONS: These findings have demonstrated that Curcumin can act as an antioxidant and antiapoptotic agent against damage induced by morphine dependence.

Preventive effect of central administration of venlafaxine on morphine physical dependence, nociception, and blood cortisol level in rat.

BACKGROUND: Chronic abuse of opiates induces dependency, but the neurobiological mechanisms of this event remain unclear. The aim of this study was to evaluate the effects of intracerebroventricular of venlafaxine on the morphine dependence and pain perception. METHODS: A total of 80 adult male rats were divided into two major groups: (1) 40 of them was divided into groups of positive control (morphine dependent) negative control (received saline) and morphine dependent groups under treatment by central administration of venlafaxine at various dosages (25, 50, or 100 µg), after drug treatment total withdrawal index (TWI), latency time of withdrawal syndrome expression and blood cortisol as marker of anxiety were measured and compared with positive control and negative control. (2) Forty rats were grouped in control; indometacin treated (5 mg/kg) and grouped which received central administration of venlafaxine at three doses (25, 50, or 100 µg) and then pain perception and expression was assessed in the writhing test (acetic acid induced abdominal constriction), tail flick, and hot plate test. RESULTS: Central administration of three doses (25, 50, or 100 µg,) of venlafaxine attenuates TWI to 47 ± 1.2, 38 ± 1.5, and 23 ± 1.1 and decrease blood cortisol level to 14 ± 1, 13.75 ± 0.5, and 12.5 ± 0.8, this decreases was significant in comparison with the positive control group (P < 0.05). Central administration of venlafaxine at mentioned doses significantly attenuates pain response with 37%, 24%, and 20% inhibition in writhing test, 69%, 34%, and 23% inhibition in hot plate test, and 29%, 23%, and 15% inhibition in tail flick test in comparison with control group (P < 0.05). CONCLUSIONS: This study suggested that central administration of venlafaxine attenuated morphine withdrawal index and can be effective in modulation of pain that was induced by morphine dependency.