Silibinin chronic treatment in a rat model of Parkinson disease: A comprehensive in-vivo evaluation and in silico molecular modeling.

BACKGROUND: Apoptosis, oxidative stress, and neuroinflammation have been linked to the onset of Parkinson's disease (PD). Although the pre-treatment effects of Silibinin on a PD model have been evaluated, in the current study we investigated the chronic therapeutic effects of Silibinin microinjection on a rat model of established parkinsonism along with behavioral and laboratory markers assessments. METHOD: Parkinsonism was induced by 6-hydroxydopamine (6-OHDA, 8 µg/2µl/rat). 21 days after that, animals were treated with Silibinin (100, 200, and 300 mg/kg for 15 consecutive days). Every two days, the bar test was used to evaluate Silibinin's anti-cataleptic properties. At the end, myeloperoxidase (MPO) activity and toll-like receptor 4 (TLR4) expression in the substantia nigra pars compacta (SNc), along with cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, caspase-3, Bax and Bcl-2 levels were assessed. We used homology modeling to predict the 3D structure of TLR4. RESULT: Silibinin's Chronic treatment, dose-dependently decreased catalepsy. MPO activity and levels of TNF-α, IL-6, and IL-1ß were reduced in Silibinin-treated rats in all three doses. Silibinin decreased Bax/Bcl-2 ratio, caspase-3, and downregulated TLR4 expression. Molecular docking revealed that there were hydrophobic and hydrogen bond interactions between the studied ligand and TLR4. Silibinin formed a stable complex with both monomer and dimer forms of TLR4. CONCLUSION: In accordance with molecular modeling and alleviation of TLR4 activity with a consequent reduction in oxidative stress, restoration of CSF inflammatory cytokine, and minimization of SNc neuronal apoptosis, long-term therapy with Silibinin offers a potential opportunity for symptomatic PD treatment.

Neuronal degeneration and oxidative stress in the SNc of 6-OHDA intoxicated rats; improving role of silymarin long-term treatment.

Progressive loss in dopaminergic neurons (DA) of substantia nigra pars compacta (SNc) leads to Parkinson's disease with a hypothesis of oxidative stress generation. The present study was conducted to determine the long-term efficacy of silymarin (SM) post-treatment on 6-OHDA-induced oxidative stress in the SNc of male rats. Male Wistar rats were received 6-OHDA (8 µg/rat) into SNc. After 3 weeks, as recovery period, the animals were treated with i.p. injection of SM at different doses of 100, 200, or 300 mg/kg for 15 days. At the end of the treatment, motor function, neuronal cell count, antioxidant enzymes, and lipid peroxidation and tyrosine hydroxylase (TH) activities were evaluated in the ventral midbrain tissue. The 6-OHDA significantly decreased (p ≤ 0.05) motor function, antioxidant enzyme activity, GSH level, and GSH/GSSG ratio and caused an augmentation in GSSG and lipid peroxidation level. The 6-OHDA also reduced the population of neurons and TH expression. The SM repaired the 6-OHDA-induced motor impairment, antioxidant enzyme suppression, and TH down-regulation. All three doses of SM could restore the MDA level to the normal range in the 6-OHDA-lesioned rats and could reversed the effect of 6-OHDA on GSH, GSSG level, and GSH/GSSG ratio. The SM treatment significantly and dose-dependently increased (p ≤ 0.001) the total number of surviving neurons in the SNc. Silymarin chronic treatment restored the brain's antioxidant capacity and salvaged neurons from oxidative stress-induced neurodegeneration. The SM could also improve motor function in parkinsonian animals by increasing TH expression. These results recommend that application of SM over initial clinical stages may depict a hopeful approach versus PD. However, more research is needed to confirm this issue.

Effects of Heracleum persicum Hydroalcoholic Extract on Insulin, Serum Anti-Oxidant Enzymes, Glucose, and Lipid Profiles in Alloxan-Induced Diabetic Rats.

BACKGROUND: Heracleum persicum (H. persicum) is a medicinal herb used in Iranian traditional medicine for its anti-toxic property. It is commonly consumed in the form of food additives and as a medicinal herbal tonic to treat liver and kidney diseases. The present study aimed to investigate the anti-oxidant, anti-diabetic, and anti-hyperlipidemic effects of H. persicum hydroalcoholic extract in alloxan-induced diabetic rats. METHODS: Adult male Wistar rats (n=30) were assigned to five groups: a normal group, a diabetic control group, and three diabetic groups treated orally with 200 and 400 mg/kg of the extract and 5 mg/kg of glibenclamide, respectively, for two weeks. Blood glucose and bodyweight were measured at the end of each week. On day 15, blood samples were collected to measure the levels of insulin, insulin growth factor-I (IGF-I), antioxidant markers for malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD), total antioxidant activity (TAS), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) using commercial kits. The data were analyzed using SPSS Software (version 22.0). RESULTS: Daily treatment with 400 mg/kg of the extract significantly reduced the blood glucose level (P<0.001) and improved bodyweight (P=0.002), insulin (P<0.001), IGF-I (P=0.024), SOD (P=0.001), GPx (P=0.009), MDA (P<0.001), TAS (P=0.006), TG (P<0.001), HDL (P=0.023), LDL (P=0.005), and VLDL (P<0.001) compared with the diabetic control group. CONCLUSION: Beneficial effects of H. persicum for the treatment of diabetes were confirmed.

Targeted Co-Delivery of Docetaxel and cMET siRNA for Treatment of Mucin1 Overexpressing Breast Cancer Cells.

Purpose: Targeted treatment of breast cancer through combination of chemotherapeutic agents and siRNA had been drawing much attention in recent researches. This study was carried out to evaluate mucin1 aptamer-conjugated chitosan nanoparticles containing docetaxel and cMET siRNA on SKBR3 cells. Methods: Nano-drugs were characterized by transmission electron microscope, Zetasizer and loading efficiency calculation. siRNA entrapment onto nanoparticles, stability of siRNA-loaded nanoparticles and conjugation of mucin1 aptamer to nanoparticles were evaluated via separate electrophoresis. Cellular uptake of the targeted nanoparticles was evaluated through GFP-plasmid expression in mucin1+ SKBR3 vs. mucin1- CHO cells. Protein expression, cell viability and gene expression were assessed by Western Blotting, MTT assay, and Quantitative Real Time-PCR, respectively. Results: Characterization of nano-drugs represented the ideal size (110.5± 3.9 nm), zeta potential (11.6± 0.8 mV), and loading efficiency of 90.7% and 88.3% for siRNA and docetaxel, respectively. Different gel electrophoresis affirmed the conjugation of aptamers to nanoparticles and entrapment of siRNA onto nanoparticles. Increased cellular uptake of aptamer-conjugated nanoparticles was confirmed by GFP expression. cMET gene silencing was confirmed by Western Blotting. The significant (p ≤0.0001) impact of combination targeted therapy vs. control on cell viability was shown. Results of Quantitative Real Time-PCR represented a remarkably decreased (p ≤0.0001) expression of the studied genes involving in tumorigenicity, metastasis, invasion, and angiogenesis (STAT3, IL8, MMP2, MMP9, and VEGF) by targeted combination treatment vs. control. Conclusion: The mucin1 aptamer-conjugated chitosan nanoparticles, containing docetaxel and cMET siRNA, is suggested for treatment of mucin1+ metastatic breast cancer cells. However, further studies should be conducted on animal models.

Silymarin prevents apoptosis through inhibiting the Bax/caspase-3 expression and suppresses toll like receptor-4 pathway in the SNc of 6-OHDA intoxicated rats.

BACKGROUND AND PURPOSE: Several lines of evidence show that apoptosis, oxidative stress and neuroinflammation are associated with the development of Parkinson's disease (PD). In the present study, we investigated the effect of pre-treatment with silymarin (SM) on oxidative stress, apoptosis and toll-like receptor 4 (TLR4) expression in substantia nigra pars copmacta (SNc) of 6-hydroxydopamine (6-OHDA)-lesioned rats. METHODS: Animals were pretreated with 100, 200 or 300 mg/kg of SM daily for 5 days and at 6th day 6-OHDA (8 µg/2 µl) was infused unilaterally into the central region of the SNc. RESULTS: 6-OHDA decreased the total glutathione and antioxidant enzymes activity in the SNc. Interestingly, we found that 6-OHDA caused to TLR4 up regulation. The SNc levels of glutathione, superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase were significantly higher in the SM pretreated rats. SM strongly decreased 6-OHDA-induced elevation of SNc apoptosis, caspase-3 and Bax/Bcl-2 ratio. Furthermore, SM markedly (p < 0.001) prevented from SNc over expression of TLR4 caused by 6-OHDA. A significantly high positive correlation was seen between TLR4 activity with caspase-3 protein levels (r = 0.896, P < 0.01), Bax protein levels (r = 0.96, P < 0.01). CONCLUSION: Pre-treatment of 6-OHDA-lesioned rats with SM reduces SNc neuronal apoptosis possibly through inhibition of TLR4 over expression. Further clinical study should be carried out to prove potential application of SM for protection against PD in susceptible individuals.

Anti-Cancer Effects of Citalopram on Hepatocellular Carcinoma Cells Occur via Cytochrome C Release and the Activation of NF-kB.

BACKGROUND: Evidence has been provided of the anti-proliferative activity of citalopram against some cancer cells. OBJECTIVE: The apoptotic impact of citalopram, an antidepressant, against liver hepatocellular carcinoma cell line HepG2 was investigated in relation to the oxidative pathway and nuclear factor (NF)κB activation. METHOD: The cytotoxic effects of citalopram on HepG2 cells were determined by MTT assay. Reactive oxygen species (ROS) formation and cytochrome c release were measured following treatment with citalopram. Apoptosis analysis and Bax and Bcl--2 mRNA and protein levels were also determined. RESULTS: The cytotoxic effects of different concentrations of citalopram on HepG2 cells were observed as a reduction in cell viability and an increase in ROS formation. Citalopram caused an increase in mitochondrial Bax levels and a decrease in Bcl2 levels and also caused cytochrome c release. Moreover, DAPI staining and flow cytometry assays revealed citalopram-induced apoptosis in HepG2 cells. Oxidant scavengers and Bay 11-7082 (an irreversible inhibitor of NFκB activation) prevented the citalopram-associated cell death, increased BAX and decreased Bcl2. CONCLUSION: Outcomes from current study suggest that citalopram might exhibit apoptotic effect against hepatocellular carcinoma cell line by induction of cell death through cytochrome c release and ROS-dependent activation of NFκB.

Mechanistic Approach for Toxic Effects of Bupropion in Primary Rat Hepatocytes.

Bupropion is a widely prescribed antidepressant/smoke cessation drug. However, hepatotoxicity is one of its side effects reported in some recipients. The mechanisms by which bupropion induces hepatotoxicity is not clear yet. This experiment was intended to assess the cytotoxic mechanisms of bupropion toward primary rat hepatocytes. Additionally, the effect of α-tocopherol succinate (ALPHA-TOS) and N-acetyl cysteine (NAC) and mitochondrial permeability transition (MPT) pore sealing agent cyclosporine A (Cs A) on this toxicity was investigated. Cell death, LDH leakage, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), and mitochondrial depolarization were examined as toxicity indicators. Results revealed that bupropion led to a surge in ROS formation, depletion of intracellular glutathione, elevation of LPO, and mitochondrial collapse. ALPHA-TOS, NAC and Cs A administration diminished the intensity of cellular damage caused by bupropion. This experiment suggests the protective role of ALPHA-TOS, NAC and Cs A against bupropion-mediated cytotoxicity possibly through their reactive radical scavenging properties and their impacts on mitochondria. Furthermore, mitochondria might be contributed to the oxidative stress response and subsequent toxicological results observed by bupropion.

In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity.

Even though citalopram is commonly used in psychiatry, there are several reports on its toxic effects. So, the current study was designed to elucidate the mechanisms of cytotoxic effects of in vitro and in vivo citalopram treatment on liver and the following cytolethal events. For in vitro experiments, freshly isolated rat hepatocytes were exposed to citalopram along with/without various agents. To do in vivo studies liver function enzyme assays and histological examination were performed. In the in vitro experiments, citalopram (500 µM) exposure demonstrated cell death, a marked elevation in ROS formation, mitochondrial potential collapse, lysosomal membrane leakiness, glutathione (GSH) depletion and lipid peroxidation. In vivo biochemistry panel assays for liver enzymes function (AST, ALT and GGTP) and histological examination confirmed citalopram (20 mg/kg)-induced damage. citalopram-induced oxidative stress cytotoxicity markers were significantly prevented by antioxidants, ROS scavengers, MPT pore sealing agents, endocytosis inhibitors, ATP generators and CYP inhibitors. Either enzyme induction or GSH depletion were concomitant with augmented citalopram-induced damage both in vivo and in vitro which were considerably ameliorated with antioxidants and CYP inhibitors. In conclusion, it is suggested that citalopram hepatotoxicity might be a result of oxidative hazard leading to mitochondrial/lysosomal toxic connection and disorders in biochemical markers which were supported by histomorphological studies.

Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats.

Purpose: The aim of the present study was to determine the ability of grape seed extract (GSE) as a powerful antioxidant in preventing adverse effect of doxorubicin (DOX) on heart function. Methods: Male rats were divided into three groups: control, DOX (2 mg/kg/48h, for 12 days) and GSE (100 mg/kg/24h, for 16 days) plus DOX. Left ventricular (LV) function and hemodynamic parameters were assessed using echocardiography, electrocardiography and a Millar pressure catheter. Histopathological analysis and in vitro antitumor activity were also evaluated. Results: DOX induced heart damage in rats through decreasing the left ventricular systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening and contractility index as demonstrated by echocardiography, electrocardiography and hemodynamic parameters relative to control group. Our data demonstrated that GSE treatment markedly attenuated DOX-induced toxicity, structural changes in myocardium and improved ventricular function. Additionally, GSE did not intervene with the antitumor effect of DOX. Conclusion: Collectively, the results suggest that GSE is potentially protective against DOX-induced toxicity in rat heart and maybe increase therapeutic index of DOX in human cancer treatment.

Effect of WR-1065 on 6-hydroxydopamine-induced catalepsy and IL-6 level in rats.

OBJECTIVES: Neuroinflammation and oxidative stress play a key role in pathogenesis of Parkinson's disease (PD). In the present study we investigated the effect of reactive oxygen species (ROS) scavenger WR-1065 on catalepsy and cerebrospinal fluid (CSF) level of interleukin 6(IL-6) and striatum superoxide dismutase (SOD) activity in 6-hydroxydopamine (6-OHDA) induced experimental model of PD. MATERIALS AND METHODS: Seventy two male Wistar rats were divided into 9 equal groups and 6-OHDA (8 µg/2 µl/rat) was infused unilaterally into substantia nigra pars copmacta (SNc) to induce PD. Catalepsy was measured by standard bar test, CSF level of IL-6 was assessed by enzyme-linked immunosorbent assay (ELISA) method and SOD activity measured by spectrophotometric method. In pre-treatment groups WR-1065 (20, 40 and 80 µg/2 µl/rat/day, for 3 days) was infused into the SNc before 6-OHDA administration and 21 days later, as a recovery period, behavioral and molecular assay tests were done. RESULTS: Our results showed that pre-treatment with WR-1065 improved (P<0.001) 6-OHDA-induced catalepsy in a dose dependent manner. In 6-OHDA-lesioned animals SOD activity in SNc and CSF level of IL-6 was decreased markedly (P<0.001) when compared with non-lesioned group, while pre-treatment with WR-1065(P<0.001) restored their levels up to the normal range. CONCLUSION: Our study indicated that pre-treatment with WR-1065 could modulate catalepsy and IL-6 level in 6-OHDA-lesioned rats. Also WR1065 could increase SOD activity up to normal range. It can be regarded as an anti-oxidative drug in prevention or adjunctive therapy of PD.

Crocin treatment prevents doxorubicin-induced cardiotoxicity in rats.

Doxorubicin (DOX)-induced cardiotoxicity is well-known as a serious complication of chemotherapy in patients with cancer. It is unknown whether crocin (CRO), main component of Crocus sativus L. (Saffron), could reduce the severity of DOX-induced cardiotoxicity. Therefore, this study was undertaken to assess the protective impact of CRO on DOX-induced cardiotoxicity in rats. The rats were divided into four groups: control, DOX (2mg/kg/48h, for 12days), and CRO groups that receiving DOX as in group 2 and CRO (20 and 40mg/kg/24h, for 20days) starting 4days prior to first DOX injection and throughout the study. Echocardiographic, electrocardiographic and hemodynamic studies, along with histopathological examination and MTT test were carried out. Our findings demonstrate that DOX resulted in cardiotoxicity manifested by decreased the left ventricular (LV) systolic and diastolic pressures, rate of rise/drop of LV pressure, ejection fraction, fractional shortening and contractility index, as compared to control group. In addition, histopathological analysis of heart confirmed adverse structural changes in myocardial cells following DOX administration. The results also showed that CRO treatment significantly improved DOX-induced heart damage, structural changes in the myocardium and ventricular function. In addition, CRO did not affect the in vitro antitumor activity of DOX. Taken together, our data confirm that CRO is protective against cardiovascular-related disorders produced by DOX, and clinical studies are needed to examine these findings in human.

Effects of WR1065 on 6-hydroxydopamine-induced motor imbalance: Possible involvement of oxidative stress and inflammatory cytokines.

Over production of reactive oxygen species (ROS) is postulated to be the main contributor in degeneration of nigrostriatal dopaminergic neurons. In this study we investigated the effects of WR1065, a free radical scavenger, on motor imbalance, oxidative stress parameters and inflammatory cytokines in CSF and brain of hemi-parkinsonian rats. Lesion of dopaminergic neurons was done by unilateral infusion of 6-hydroxydopamine into the central region of the substentia nigra pars compacta (SNc) to induce hemi-parkinsonism and motor imbalance in rats. WR1065 (20, 40 and 80µg/2µl/rat) was administered three days before 6-OHDA administration. After three weeks behavioral study was performed and then brain and CSF samples were collected to assess tumor necrosis factor (TNFα), interlukin (IL-1ß), reduced glutathione (GSH), and malondialdehyde (MDA). WR1065 pre-treatment in rats before receiving 6-OHDA, improved significantly motor impairment and caused reduction of MDA and inflammatory cytokines TNFα and IL-1ß levels, while GSH level significantly increased when compared with lesioned rats. Our study indicated that WR1065 could improve 6-OHDA-induced motor imbalance. Furthermore, it decreased lipid peroxidation and inflammatory cytokines and restored the level of GSH up to normal range. We suggest that WR1065 can be proposed as a potential neuroprotective agent in motor impairments of PD. However to prove this hypothesis more clinical trial studies should be done.

Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction.

Purpose: Depression is a public disorder worldwide. Despite the widespread use of venlafaxine in the treatment of depression, it has been associated with the incidence of toxicities. Hence, the goal of the current investigation was to evaluate the mechanisms of venlafaxine-induced cell death in the model of the freshly isolated rat hepatocytes. Methods: Collagenase-perfused rat hepatocytes were treated with venlafaxine and other agents. Cell damage, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential decline, lysosomal damage, glutathione (GSH) level were analyzed. Moreover, rat liver mitochondria were isolated through differential centrifugation to assess respiratory chain functionality. Results: Our results demonstrated that venlafaxine could induce ROS formation followed by lipid peroxidation, cellular GSH content depletion, elevated GSSG level, loss of lysosmal membrane integrity, MMP collapse and finally cell death in a concentration-dependent manner. N-acetyl cysteine, taurine and quercetine significantly decreased the aforementioned venlafaxine-induced cellular events. Also, radical scavenger (butylatedhydroxytoluene and α-tocopherol), CYP2E1 inhibitor (4-methylpyrazole), lysosomotropic agents (methylamine and chloroquine), ATP generators (L-gluthamine and fructose) and mitochondrial pore sealing agents (trifluoperazine and L-carnitine) considerably reduced cytotoxicity, ROS generation and lysosomal leakage following venlafaxine treatment. Mitochondrion dysfunction was concomitant with the blockade of the electron transfer complexes II and IV of the mitochondrial respiratory system. Conclusion: Therefore, our data indicate that venlafaxine induces oxidative stress towards hepatocytes and our findings provide evidence to propose that mitochondria and lysosomes are of the primary targets in venlafaxine-mediated cell damage.

Cardioprotective Effect of Phenytoin on Doxorubicin-induced Cardiac Toxicity in a Rat Model.

Doxorubicin (DOX) is an effective anticancer agent, but adverse cardiotoxic effects limit its use. Compounds reducing DOX cardiotoxicity could improve its therapeutic index. This study investigated the protective effects of phenytoin (Phen) for DOX-induced cardiomyopathy. Male Wistar rats were randomized into 5 groups to receive either saline, DOX (2 mg/kg per 48 hours, 6 doses, intraperitoneally) or DOX + Phen (5, 10, or 20 mg/kg/d, starting 4 days before DOX, intraperitoneally). The animals were assessed 24 hours after the last injection. Left ventricular (LV) function and hemodynamic parameters were assessed using transthoracic echocardiography, electrocardiography, and a Millar pressure catheter. Histopathological studies were performed, and the effect of Phen on the cytotoxicity of DOX was evaluated in vitro for the human breast adenocarcinoma cell line. DOX-impaired LV function significantly decreased the LV systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening, and contractility index. DOX caused structural changes in myocardial cells. Treatment with Phen decreased DOX-induced toxicity, significantly improved ventricular function, and ameliorated structural changes in the myocardium. Phen also did not interfere with the antitumor effect of DOX. The results confirm the cardioprotective effect of Phen against DOX-induced cardiomyopathy without removing antitumor effect of DOX.

Comparison of the Analgesic Effect of Diclofenac Sodium-Eudragit(®) RS100 Solid Dispersion and Nanoparticles Using Formalin Test in the Rats.

PURPOSE: In this study the intensity and duration of analgesic effect of diclofenac Na - Eudragit(®) RS100 solid dispersion and nanoparticles were evaluated by using formalin test in the rats. METHODS: The animals received different formulations of diclofenac Na and subsequently 50 µl of formalin solution (2.5%) was injected subcutaneously in the right paws after 1 h, 2 h and 3 h. The paw licking behavior was then evaluated in two phases. A dose of 20 mg/kg of pure diclofenac Na powder was determined as effective dose. RESULTS: In the first phase, in term of reduced paw licking time, no significant differences were found in any of the groups compared to the control group. However, in the second phase, the animals which received pure drug powder and the physical mixture of diclofenac Na with Eudragit(®) RS100 showed significant differences at the first and second hours. In the animals received the nanoparticles and solid dispersion, significant differences were observed in the third hour compared to the control group. CONCLUSION: The analgesic effect of diclofenac Na could be improved by formulating its nanoparticles and solid dispersion with Eudragit(®) RS100. However, the nanoparticles revealed significantly higher analgesic effect than solid dispersion.

Short-Term Treatment with Silymarin Improved 6-OHDA-Induced Catalepsy and Motor Imbalance in Hemi-Parkisonian Rats.

PURPOSE: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor abnormalities, which include tremor, muscle stiffness, paucity of voluntary movements, and postural instability. Silymarin (SM) or milk thistle extract, is known to own antioxidative, anti-apoptotic, anti-inflammatory and neuroprotective effects. In the present study, we investigated the effect of intraperitoneal (i.p) administration of SM, on 6-OHDA-induced motor-impairments (catalepsy and imbalance) in the rats. METHODS: Experimental model of PD was induced by unilateral infusion of 6-hydroxydopamine (6-OHDA; 8 µg/2 µl/rat) into the central region of the substantia nigra pars compacta (SNc). Catalepsy and motor coordination were assessed by using of bar test and rotarod respectively. RESULTS: The results showed a significant (p<0.001) increase in catalepsy of 6-OHDA-lesioned rats whereas; in SM (100, 200 and 300 mg/kg, i.p for 5 days) treated hemi-parkinsonian rats catalepsy was decreased markedly (p<0.001). Furthermore, there was a significant (p<0.001) increase in motor-imbalance of 6-OHDA-lesioned rats. SM improved motor coordination significantly (p<0.001) in a dose dependent manner and increased motor balance. CONCLUSION: In conclusion, we found that short-term treatment with SM could improve 6-OHDA-induced catalepsy and motor imbalance in rats. We suggest that SM can be used as adjunctive therapy along with commonly used anti-parkinsonian drugs. However, further clinical trial studies should be carried out to prove this hypothesis.

Effect of Buspirone, Fluoxetine and 8-OH-DPAT on Striatal Expression of Bax, Caspase-3 and Bcl-2 Proteins in 6-Hydroxydopamine-Induced Hemi-Parkinsonian Rats.

PURPOSE: The exact pathogenesis of sporadic parkinson's disease (PD) is still unclear. Numerous evidences suggest involvement of apoptosis in the death of dopaminergic neurons. In this study we investigated the effect of sub-chronic administration of buspirone, fluoxetine and 8-hydroxy-2-[di-n-propylamino]tetralin (8-OH-DPAT) in 6-hydroxydopamine (6-OHDA)-lesioned rats and assayed striatal concentrations of apoptotic (Bax, Caspase3) and anti-apoptotic (Bcl-2) proteins. METHODS: 6-OHDA (8µg/2µl/rat) was injected unilaterally into the central region of the substantia nigra pars copmacta (SNc) of male Wistar rats and then, after 21 days lesioned rats were treated with intraperitonel (i.p) 1 mg/kg injections of buspirone, fluoxetine and 8-OH-DPAT for 10 consecutive days. Striatum of rats was removed at tenth day of drugs administration and were analyzed by western blotting method to measure Bax, caspase3 and Bcl-2 expression. RESULTS: The results showed that the expression of Bax and caspase3 proteins was increased three weeks after 6-OHDA injection while they were decreased significantly in parkinsonian rats which were treated by buspirone, fluoxetine and 8-OH-DPAT. Bcl-2 was decreased and increased in parkinsonian rats and parkinsonian rats treated with buspirone, fluoxetine and 8-OH-DPAT, respectively. CONCLUSION: Our study indicates that sub-chronic administration of serotonergic drugs such as buspirone, fluoxetine and 8-OH-DPAT restores striatal concentration of apoptotic and anti-apoptotic factors to the basal levels of normal non-lesioned rats. We suggest that these drugs can be used as a potential adjunctive therapy in PD through attenuating neuronal apoptotic process.

Testosterone ameliorates streptozotocin-induced memory impairment in male rats.

AIM: To study the effects of testosterone on streptozotocin (STZ)-induced memory impairment in male rats. METHODS: Adult male Wistar rats were intracerebroventricularly (icv) infused with STZ (750 µg) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of STZ. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. Testosterone (1 mg·kg(-1)·d(-1), sc), the androgen receptor antagonist flutamide (10 mg·kg(-1)·d(-1), ip), the estrogen receptor antagonist tamoxifen (1 mg·kg(-1)·d(-1), ip) or the aromatase inhibitor letrozole (4 mg·kg(-1)·d(-1), ip) were administered for 6 d after the first injection of STZ. RESULTS: STZ administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in STZ-treated rats. Administration of flutamide, letrozole or tamoxifen significantly impaired the memory in intact rats, and significantly attenuated the testosterone replacement in improving STZ- and castration-induced memory impairment. CONCLUSION: Testosterone administration ameliorates STZ- and castration-induced memory impairment in male Wistar rats.