Bone marrow mesenchymal stem cells improve cognitive impairments induced by methamphetamine in rats and reduce relapse.

Introduction: Chronic exposure to methamphetamine (Meth) results in permanent central nervous system damage and learning and memory dysfunction. This study aimed at investigating the therapeutic effects of bone marrow mesenchymal stem cells (BMMSCs) on cognitive impairments in Meth addicted rats and comparing intravenous (IV) delivery with intranasal (IN) delivery of BMMSCs. Methods: Adult Wistar rats were randomly divided into 6 groups; Control; Meth-addicted; IV-BMMSC (Meth administered and received IV BMMSCs); IN-BMMSC (Meth administered and received IN BMMSCs); IV-PBS (Meth administered and received IV Phosphate-buffered saline (PBS); IN-PBS (Meth administered and received IN PBS). BMMSCs were isolated, expanded in vitro, immunophenotyped, labeled, and administered to BMMSCs-treated groups (2 × 106 cells). The therapeutic effect of BMMSCs was measured using Morris water maze and Shuttle Box. Moreover, relapse-reduction was evaluated by conditioning place preference after 2 weeks following BMMSCs administration. The expression of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) in rat hippocampus was assessed using immunohistochemistry method. Results: Administration of BMMSCs caused a significant improvement in the learning and memory functions of Meth-addicted rats and reduced the relapse (P<0.01). In behavioral tests, comparison of IV and IN BMMSC-treated groups did not show any significant difference. Administration of BMMSCs improved the protein level of BDNF and GDNF in the hippocampus, as well as causing behavioral improvement (P<0.001). Conclusion: BMMSC administration might be a helpful and feasible method to treat Meth-induced brain injuries in rats and to reduce relapse. BMMSCs were significantly higher in IV-treated group compared to the IN route. Moreover, the expression of BDNF and GDNF was higher in IN-treated rats compared with IV treated group.

Berberine hydrochloride improves cognitive deficiency through hippocampal up-regulation of neurotrophins following inhalant self-administration of methamphetamine.

Objectives: Chronic methamphetamine (METH) abuse is recognized as an important risk factor for cognitive impairment. A plant-based isoquinoline alkaloid, Berberine hydrochloride (BER), shows memory and cognition enhancement properties. Due to the aim of the present study which is to investigate the influence of BER administration on METH-induced cognitive deficits, we investigated neurotrophin signaling including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) as a possible mechanism by which BER exerts its cognitive improvement influences. Materials and Methods: In this experimental study, thirty-two male Wistar rats were randomly classified into four groups, including non-treated control, intubated control, METH-inhaled, and METH-inhaled + BER-intubated. Rats in the METH-inhaled group underwent METH inhalation for 14 days, and the BER-inhaled and BER-intubated rats were intubated (100mg/kg) for the following three weeks. A novel object recognition task (NORt) was carried out on days 36 and 37. Rats were sacrificed for histological preparations after the behavioral tests. Neurotrophic factors, including GDNF and BDNF, were evaluated by immunofluorescence staining in the hippocampus. Results: This experiment indicated a dramatic improvement in cognitive deficits associated with chronic METH abuse (P<0.001). Furthermore, a significant decrease in the expression of both neurotrophins, GDNF (P<0.001) and BDNF (P<0.001), was observed in the METH-inhaled group compared with the METH-inhaled group treated with BER and non-treated control group. Conclusion: Activation of neurotrophic factors after BER administration resulted in improvement of METH-induced cognitive deficits. Therefore, BER may be considered a promising treatment for METH users who experience cognition deficits.

Neuroprotective Effects of Berberine Hydrochloride on Methamphetamine-induced Cognitive Dysfunction: Immunohistochemical and Behavioral Studies in Rats.

Introduction: Methamphetamine (MA) as an addictive psychostimulant drug affects the central nervous system. The current research aimed to evaluate the impact of berberine hydrochloride on improving cognitive function and neuroprotective effects in rats addicted to MA. Methods: In this study, 27 male Wistar rats were randomly assigned to three groups, including control, MA addiction, and MA addiction with berberine hydrochloride (100 mg/kg/d) orally during the three weeks of withdrawal. Two groups received self-administered inhaled MA for two weeks (up to 10 mg/kg). Following the experimental procedures, a Morris water maze (MWM) and shuttle box were used to assess memory, and hippocampal sections from the animals were examined for caspase-3, Ki-67, and glial fibrillary acidic protein (GFAP) expression. Results: The obtained results from the Morris water maze (MWM) showed that berberine hydrochloride decreases (P<0.01) the distance moved and the time spent to reach the hidden platform in the four-day learning trails phase and significant differences were observed in the distance moved, spent time, and frequency of motion in target quadrant on probe test day between groups. Berberine hydrochloride also reduced the latency of animals entering the dark chamber in the treated group compared to the control group (P<0.05). A significant decrease in activation of caspases-3, higher percentages of Ki-67 expression, and an increase in glial fibrillary acidic protein (GFAP) expression of cells was observed in the addicted group compared to the berberine-treated and control groups (P<0.05). Conclusion: Administration of berberine hydrochloride for 3 weeks improves cognitive function in MA addiction and it has potential neuroprotective efficacy. Highlights: Methamphetamine (MA) as an addictive psychostimulant drug affects the central nervous system.The berberine hydrochloride effects on improving cognitive function and neuroprotective.No approved pharmacotherapy, as well as confirmed medication, is available to treat MA abuse. Plain Language Summary: Methamphetamine (MA) is known as a strong addictive stimulant with high addiction and no approved pharmaco-therapy, as well as confirmed medication, is available to treat MA abuse. The study on the long-term effect of MA exposure on cognitive function during an object recognition memory test showed cognitive dysfunction after MA exposure. Berberine can reduce induced amnesia, which can be due to the increased peripheral and central cholinergic neuronal system functions, in addition, the most important mechanism in the protective effect of berberine against amnesia is the inhabitation of inflammation; however, the berberine impact on cells should be more investigated.

Metabolite Alternations in the Dopamine Circuit Associated with Methamphetamine-Related Psychotic Symptoms: A Proton Magnetic Resonance Spectroscopy Study.

Objective: Chronic METH use results in neurodegenerative alternations in the human brain. The present study aimed to assess the long-term METH impact on brain metabolite concentrations in cases meeting the DSM-5 criteria regarding METH use. Method: We recruited 42 METH users meeting the DSM-5 criteria and 21 healthy controls. Psychotic signs were measured using the Positive and Negative Syndrome Scale (PANSS). Proton magnetic resonance spectroscopy (1HMRS) evaluating Myo-inositol (Ml), Choline (Cho), Glutamine plus Glutamate (Glx), N-acetyl aspartate (NAA), and Creatine (Cre) were obtained in the dopaminergic pathway (Frontal Cortex, Substantia nigra, Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), Hippocampus, Striatum,) the subjects. All participants collected urine specimens for 24 hours to measure presence of specific metabolites including METH metabolite level, 5-Hydroxy indoleacetic acid metabolite (for serotonin level monitoring), and metanephrine metabolite (for dopamine level monitoring). Results: Dopamine and Serotonin increased in the METH group (P < 0.001). METH caused an increase in the Cre (P < 0.001) and a decline in the Glx (P < 0.001), NAA (P = 0.008), and MI (P < 0.001) metabolite concentrations of dopamine circuits in METH users in comparison with healthy subjects. We found no change in Cho metabolite concentration. Psychological data and the neurometabolite concentrations in the studied area of the brain were significantly correlated. Conclusion: There is an association between METH use and active neurodegeneration in the dopamine circuit, and it causes serious mental illness. 1HMRS can detect patient's deterioration and progression of disease as well as follow-up management in patients with METH use disorder.

Effects of berberine hydrochloride on methamphetamine-induced anxiety behaviors and relapse in rats.

OBJECTIVES: This research aimed at evaluating the effect of berberine hydrochloride on anxiety-related behaviors induced by methamphetamine (METH) in rats, assessing relapse and neuroprotective effects. MATERIALS AND METHODS: 27 male Wistar rats were randomly assigned into groups of Control, METH-withdrawal (METH addiction and subsequent withdrawal), and METH addiction with berberine hydrochloride oral treatment (100 mg/kg/per day) during the three weeks of withdrawal. Two groups received inhaled METH self-administration for two weeks (up to 10 mg/kg). The elevated plus maze (EPM) test and open field test (OFT) were carried out one day after the last berberine treatment and relapse was assessed by conditional place preference (CPP) test. TUNEL assay and immunofluorescence staining for NF-κB, TLR4, Sirt1, and α-actin expression in the hippocampus were tested. RESULTS: After 3 weeks withdrawal, berberine hydrochloride decreased locomotor activity and reduced anxiety-related behaviors in comparison with the METH-withdrawal group (P<0.001). The obtained results from CPP showed that berberine significantly reduced relapse (P<0.01). Significantly decrease in activation of TLR4, Sirt1, and α-actin in METH-withdrawal group was found and the percentage of TLR4, Sirt1, and α-actin improved in berberine-treated group (P<0.001). A significant activity rise of NF-κB of cells in the METH-withdrawal group was detected compared to berberine-treated and control groups (P<0.001). CONCLUSION: Treatment with berberine hydrochloride via modulating neuroinflammation may be considered as a potential new medication for the treatment of METH addiction and relapse. The histological assays supported the neuroprotective effects of berberine in the hippocampus.

Effects of Urtica dioica supplementation on blood lipids, hepatic enzymes and nitric oxide levels in type 2 diabetic patients: A double blind, randomized clinical trial.

OBJECTIVE: Oxidative stress plays an important role in the development of diabetic complications including metabolic abnormality-induced diabetic micro-vascular and macro-vascular complications. Urtica dioica L. (U. dioica) has been traditionally used in Iranian medicine as an herbal remedy for hypoglycemic or due to its anti-inflammatory properties. The aim of the present study was to evaluate the effects of hydro-alcoholic extract of U. dioica on blood lipids, hepatic enzymes and nitric oxide levels in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: 50 women with type 2 diabetes participated in this study and were randomly divided into two groups namely, control and intervention groups. Control group received placebo and intervention group received hydro-alcoholic extract of U. dioica. Before and after 8 weeks of continuous treatment, some biochemical serum levels including FPG, TG, SGPT, SGOT, HDL, LDL, SOD and NO were measured. RESULTS: The results indicated that after 8 weeks, in the intervention group, FPG, TG, and SGPT levels significantly decreased and HDL, NO and SOD levels significantly increased as compared to the control group. CONCLUSION: Our results encourage the use of hydro-alcoholic extract of U. dioica as an antioxidant agent for additional therapy of diabetes as hydro-alcoholic extract of U. dioica may decrease risk factors of cardiovascular incidence and other complications in patients with diabetes mellitus.

Analysis of Chemokine Receptor Gene Expression in Esophageal Cancer Cells Compared with Breast Cancer with Insights into Metastasis.

BACKGROUND: Chemokine receptors have been shown to play an important role in the development and metastatic spread of various malignancies. In this study, the gene expression profile of some key chemokine receptors involved in metastasis has been investigated in esophageal and breast cancer cell lines. METHODS: In a descriptive study, gene expression profile of CCR1, CCR6, CCR7, CCR9, CXCR1, and CXCR4 in human esophageal cancer cell line (KYSE-30) and human breast cancer cell line (MCF7) were analyzed using real-time PCR and their results were compared accordingly. RESULTS: We demonstrated for the first time the expression of CCR1, CCR6, CCR7, CCR9, CXCR1, and CXCR4 at transcriptional level in human esophageal cancer cell line. The expression of CCR1, CCR7 and CXCR4 were lower in esophageal compared with breast cancer cells, although without significant difference. CCR9 was highly expressed in esophageal cancer cells as compared to the breast cancer cells (P < 0.05). Similarly, the expression of CCR6 and CXCR1 were higher, although without significant difference. CONCLUSION: Esophageal cancer cells like breast cancer express some key chemokine receptors involved in metastasis. Targeting of proposed receptors in esophageal cancer may be a novel strategy for prevention of cancer metastasis.

Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia.

Hydrogen sulfide (H(2)S), a well-known toxic gas, is regarded as endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. Recent studies have shown relatively high concentrations of hydrogen sulfide (H(2)S) in the brain and also cytoprotective effects of endogenous and exogenous H(2)S in models of in vitro and in vivo ischemic injury. H(2)S protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic mediator and by improving neurological function. Moreover, it protects neurons from glutamate toxicity. Therefore, the present study aimed to determine whether H(2)S provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and NaHS (H(2)S donor; 1 and 5 mg) were intraperitoneally injected (IP) at the beginning of ischemia. Infarct volume, brain edema, and apoptosis were assessed 24 h after MCAO.Treatment with NaHS at doses of 1 and 5 mg markedly reduced total infarct volumes by 29 and 51 %, respectively (P < 0.001). In addition, NaHS at doses of 1 and 5 mg reduced brain edema (P < 0.05) and inhibited apoptosis by decreasing positive TUNEL cells (P < 0.001).The present study shows that treatment with H(2)S reduces brain injuries and postischemic cerebral edema in a dose-dependent manner likely through the blocking programmed cell death.We propose that H(2)S might be a promising therapeutic target for stroke, although more researches are necessary to take into account the potential therapeutic effects of H(2)S in stroke patients.

The sesame lignan sesamin attenuates vascular dysfunction in streptozotocin diabetic rats: involvement of nitric oxide and oxidative stress.

The effect of chronic administration of sesamin was studied on aortic reactivity of streptozotocin diabetic rats. Male diabetic rats received sesamin for 7 weeks after diabetes induction. Contractile responses to KCl and phenylephrine and relaxation response to acetylcholine were obtained from aortic rings. Maximum contractile response of endothelium-intact rings to phenylephrine was significantly lower in sesamin-treated diabetic rats relative to untreated diabetics and endothelium removal abolished this difference. Meanwhile, endothelium-dependent relaxation to acetylcholine was significantly higher in sesamin-treated diabetic rats as compared to diabetic ones and pretreatment of rings with nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester significantly attenuated the observed response. Two-month diabetes also resulted in an elevation of malondialdehyde and decreased superoxide dismutase activity and sesamin treatment significantly improved these changes. Therefore, chronic treatment of diabetic rats with sesamin could prevent some abnormal changes in vascular reactivity in diabetic rats through nitric oxide and via attenuation of oxidative stress and tissue integrity of endothelium is necessary for its beneficial effect.

Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats.

Chronic diabetes mellitus initiates apoptosis and negatively affects synaptic plasticity in the hippocampus with ensuing impairments of learning and memory. Berberine, an isoquinoline alkaloid, exhibits anti-diabetic, antioxidant and nootropic effects. This study was conducted to evaluate the effect of berberine on hippocampal CA1 neuronal apoptosis, synaptic plasticity and learning and memory of streptozotocin (STZ)-diabetic rats. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was recorded for assessment of synaptic plasticity and field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. PS amplitude and fEPSP significantly decreased in diabetic group versus control, and chronic berberine treatment (100mg/kg/day, p.o.) restored PS amplitude and fEPSP and ameliorated learning and memory impairment and attenuated apoptosis of pyramidal neurons in the CA1 area, as determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling method. In summary, chronic berberine treatment of STZ-diabetic rats significantly ameliorates learning and memory impairment and part of its beneficial effect could be attributed to improvement of synaptic dysfunction and anti-apoptotic property.