Pathogenic mechanisms following ischemic stroke.

Stroke is the second most common cause of death and the leading cause of disability worldwide. Brain injury following stroke results from a complex series of pathophysiological events including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis. Moreover, there is a mechanistic link between brain ischemia, innate and adaptive immune cells, intracranial atherosclerosis, and also the gut microbiota in modifying the cerebral responses to ischemic insult. There are very few treatments for stroke injuries, partly owing to an incomplete understanding of the diverse cellular and molecular changes that occur following ischemic stroke and that are responsible for neuronal death. Experimental discoveries have begun to define the cellular and molecular mechanisms involved in stroke injury, leading to the development of numerous agents that target various injury pathways. In the present article, we review the underlying pathophysiology of ischemic stroke and reveal the intertwined pathways that are promising therapeutic targets.

Evaluation of the role of striatal cannabinoid CB1 receptors on movement activity of parkinsonian rats induced by reserpine.

It has been observed cannabinoid CB1 receptor signalling and the levels of endocannabinoid ligands significantly increased in the basal ganglia and cerebrospinal fluids of Parkinson's disease (PD) patients. These evidences suggest that the blocking of cannabinoid CB1 receptors might be beneficial to improve movement disorders as a sign of PD. In this study, a dose-response study of the effects of intrastriatal injection of a cannabinoid CB1 receptor antagonist, AM251 and agonist, ACPA, on movement activity was performed by measuring the catalepsy of reserpinized and non-PD (normal) rats with bar test. Also the effect of co-administration the most effective dose of AM251 and several doses of ACPA were assessed. AM251 decreases the reserpine induced catalepsy in dose dependent manner and ACPA causes catalepsy in normal rats in dose dependant manner as well. AM251 significantly reverse the cataleptic effect in all three groups (1, 10, 100 ng/rat) that received ACPA. These results support this theory that cannabinoid CB1 receptor antagonists might be useful to alleviate movement disorder in PD. Also continuance of ACPA induced catalepsy in rats after AM251 injection can indicate that other neurotransmitters or receptors interfere in ACPA induced catalepsy. Based on the present finding there is an incomplete overlapping between cannabinoid CB1 receptor agonist and antagonist effects.

Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents.

Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke.

Vanillic acid attenuates effects of transient bilateral common carotid occlusion and reperfusion in rats.

Cerebral hypoperfusion induced by transient bilateral common carotid arteries occlusion (tBCCAO), is associated with deleterious alterations in several physiological parameters of the animals. This study aims to investigate the effects of vanillic acid (VA) on memory impairment, locomotion and exploratory deficits, as well as histological and hippocampal long-term potentiation (LTP) injuries induced by tBCCAO procedure followed by reperfusion (BCCAO/R) in rats. Adult male Wistar rats (250-300g) were divided randomly into four groups: Sham-Operated group "Sham"; Vehicle+BCCAO/R group "BCCAO/R"; Vehicle+ Vanillic acid group "VA"; VA (100mg/kg) +BCCAO/R group "VA +BCCAO/R". Cerebral hypoperfusion was induced after 14days of pretreatment with VA and/or normal saline. To induce the animal model of hypoperfusion, bilateral common carotid arteries were occluded for 30min, followed by 72h of reperfusion. Subsequently, behavioral, histopathological and electrophysiological parameters were evaluated after BCCAO/R. Data showed that pretreatment of VA markedly improved locomotion in tBCCAO rats compared with the untreated BCCAO/R rats (p<0.05). Moreover, pretreatment of VA significantly ameliorated memory impairment in "VA+BCCAO/R" group compared with the "BCCAO/R" group (P<0.01). The field excitatory postsynaptic potential (fEPSP) amplitude and slope were significantly decreased in "BCCAO/R" group compared with Sham group (P<0.001). Data indicate that fEPSP amplitude and slope were increased in "VA+BCCAO/R" group compared with the "BCCAO/R" group (P<0.001). Furthermore, histopathological observation in VA pretreated tBCCAO rats showing markedly attenuated of cell death (P<0.01) and arrangement of CA1 neurons as compared with the untreated BCCAO/R rats. Our data confirm the protective role of VA against transient cerebral ischemia and reperfusion in rats. Moreover, it proposes that VA has a beneficial role in cerebrovascular insufficiency states.

Anti-diabetic effect of betulinic acid on streptozotocin-nicotinamide induced diabetic male mouse model

ABSTRACT Diabetes is a metabolic disease caused by abnormal insulin secretion or action. In the present study, the effects of betulinic acid (BA, a triterpene) are evaluated on glucose, α-amylase and plasma insulin levels, insulin resistance and the histopathology of pancreatic islets in streptozotocin-nicotinamide (STZ-NA) diabetic mice. Seventy adult male NMRI mice were randomly divided into seven groups: control, sham, diabetic, diabetic treated with BA (10, 20 and 40 mg/kg) and diabetic treated with metformin (200 mg/kg). Diabetes was induced in mice by intraperitoneal injection of streptozotocin 50 mg/kg after a dose of nicotinamide 120 mg/kg. Two weeks after treatment with BA, blood samples were collected for measuring glucose, α-amylase and insulin levels, and the pancreas was isolated for histopathology evaluation. Diabetes reduced the number and diameter of pancreatic islets, and increased α-amylase and insulin resistance. BA treatment reduced blood glucose, α-amylase and improved insulin sensitivity as well as pancreas histopathology. In addition, BA showed stronger effects on the pancreatic histology and insulin resistance compared to the metformin group

Nanosized tamoxifen-porphyrin-glucose [TPG] conjugate: novel selective anti-breast-cancer agent, synthesis and in vitro evaluations.

Tumor and especially breast cancer is among the most common causes of death worldwide. Finding novel nanosized therapeutic compounds have important role to decrease the chance of death and increase the survival. Cancer cells are highly attractive to glucose [with a nanosize bimolecular structure 1nm] as an energy source more than normal cell and nanosized therapeutics due to possessing different pharmacokinetic and pharmacodynamic have advantageous over classical dosage forms in cancer therapy. The aim of the study was to synthesize Glucosamin-Porphyrin-Tamoxifen [TPG] nanosized complex as a novel selective biocompatible anti breast cancer agent. After the synthesis procedure, this complex was purified and then tested In Vitro on breast cancer cells [MCF-7] in the absence or presence of the red light and found totally successful. The results showed a good anti breast cancer activity mediated by the activation of TNF-α and necrosis/apoptosis pathways for the nanosized complex with no alteration effects on blood PT/APTT and glucose or hexokinase levels/ activity. TPG nanoconjugate seems to be very good opponents to current anti breast cancer drugs and needs to be further investigated in near future.

Administration of venlafaxine after chronic methadone detoxification blocks post-depression relapse in rats

ABSTRACT Relapse is highly prevalent after detoxification and depression. Due to the advantages of venlafaxine compared with other antidepressants, it is expected that venlafaxine administration may reduce relapse after detoxification and depression. This study aimed to evaluate the effects of venlafaxine on depression-induced relapse to morphine dependence after methadone detoxification. Eighty Sprague-Dawley rats were habituated and conditioned with morphine (10 mg/kg, S.C., for 4 days). After that, primary forced swimming and conditioned place preference (CPP) were tested. They were followed by methadone (70 mg/kg/day, P.O., for 7 days) administration, extinguishing, forced swimming stress (FSS) and administration of venlafaxine (80 mg/kg/day, I.P., for 7 days). Finally same tests were performed. Administration of venlafaxine resulted in a decrement in final preference scores associated with a prime morphine injection (PMI) compared to the primary scores in methadone treated (MTD+) animals. In a swimming test, venlafaxine increased the amount of final floating and decreased final activity scores compared with the primary scores after administration of methadone. Venlafaxine reduced locomotor activity in MTD+ animals in the final test with PMI. There was a positive correlation between the final activity and preference scores after PMI. In conclusion, venlafaxine improved anxiety and depression-induced relapse on methadone detoxified rats.

Two-Point Discrimination Test in the Treatment of Right-handed Females with Lumbosacral Radiculopathy.

Non-somatic causes of pain may aggravate painful complaints and complicate the conservative management of diseases such as lumbo-sacral disk root disease. The two-point discrimination test has been used for assessment of diseases, which change patients' skin sensation. This study aims to find out how applicable is two-point discrimination test in the conservative treatment of lumbo-sacral disk diseases. Twenty right-handed females suffering from unilateral lumbo-sacral disk disease were admitted for a conservative treatment from 2006 to 2009. The treatment consisted of a week bed rest, physiotherapy, and medication. They were subjected to straight leg raising tests, and their pains were evaluated using visual analog scale. The values of two-point discrimination test were obtained bilaterally for L(4), L(5) and S(1 )dermatomes. Changes between the involved and intact lower limbs as well as values of two-point discrimination test before and after the treatment were also compared. In addition, the correlation between the outcome of two-point discrimination, straight leg raising tests, or pain scores were evaluated. There was a significant (P<0.001) difference between the changes in the values of two-point discrimination test, pain scales, or straight leg raising tests in the involved and intact limbs before and after the treatment. However, correlation among variables did not reach statistical significance (P<0.94, r=0.017). The results indicated that although two-point discrimination test is a feasible and objective tool to evaluate patients' improvements during the conservative management of lumbo-sacral disk diseases, there were no strong correlations between two-point discrimination test and straight leg raising tests, or pain scale.

Effects of aspirin and celecoxib on rigidity in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a degenerative neurodopaminergic disease in nigrostriatum pathway of human and is responsible for most of the movement disorders. Increasing evidence suggests that an inflammatory reaction accompanies the pathological processes caused by Cyclooxygenase (COX) seen in many neurodegenerative disorders, including PD and according to the recent researches chronic use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) decreases the risk of PD in human. In the study the rat left Substantia Nigra Pars Compacta (SNc) have been destroyed using electrical lesion (1 mA; DC; 8 Sec) to induce PD model. Then aspirin (30, 60 mg kg(-1)) and celecoxib (4, 8 mg kg(-1)) have been administrated orally to parkinsonian rats. When the animals were suffered to PD Murprogo's Method evaluated the rigidity ofparkinsonian rats. Both selective COX-2 inhibitor (celecoxib) and non-selective COX-2 inhibitor (aspirin) decreased the rigidity of parkinsonian rats p<0.05 but rigidity recovery after administration the selective COX-2 inhibitor was more than non-selective COX-2 inhibitor. These findings are additional pharmacological information which has suggested the use of NSAIDs as alternative way to treat the rigidity of PD.