The extracellular vesicles-derived from mesenchymal stromal cells: A new therapeutic option in regenerative medicine.

Mesenchymal stem cells (MSCs) are adult multipotent cells that due to their ability to homing to damaged tissues and differentiate into specialized cells, are remarkable cells in the field of regenerative medicine. It's suggested that the predominant mechanism of MSCs in tissue repair might be related to their paracrine activity. The utilization of MSCs for tissue repair is initially based on the differentiation ability of these cells; however now it has been revealed that only a small fraction of the transplanted MSCs actually fuse and survive in host tissues. Indeed, MSCs supply the microenvironment with the secretion of soluble trophic factors, survival signals and the release of extracellular vesicles (EVs) such as exosome. Also, the paracrine activity of EVs could mediate the cellular communication to induce cell-differentiation/self-renewal. Recent findings suggest that EVs released by MSCs may also be critical in the physiological function of these cells. This review provides an overview of MSC-derived extracellular vesicles as a hopeful opportunity to advance novel cell-free therapy strategies that might prevail over the obstacles and risks associated with the use of native or engineered stem cells. EVs are very stable; they can pass the biological barriers without rejection and can shuttle bioactive molecules from one cell to another, causing the exchange of genetic information and reprogramming of the recipient cells. Moreover, extracellular vesicles may provide therapeutic cargo for a wide range of diseases and cancer therapy.

Synthesis, receptor affinity and effect on pentylenetetrazole-induced seizure threshold of novel benzodiazepine analogues: 3-Substituted 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles and 2-amino-5-(phenoxybenzyl)-1,3,4-oxadiazoles.

The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles, possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles were designed and synthesized as novel benzodiazepine analogues. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the reference drug. Among them, 5-(4-chloro-2-(2-fluorophenoxy)benzyl)-3-benzylthio-4H-1,2,4-triazole (8l) showed the highest affinity (IC50=0.892 nM) relative to diazepam (IC50=2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the reference drug.

Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system.

Neuropathic pain is one of the most common complications of diabetes mellitus. As efficacy and tolerability of current therapy for neuropathic pain are not ideal, we need to develop the novel drug for better treatment. Curcumin as a natural flavonoid from Curcuma longa has considerable effects on nervous system such as, antidepressant, antinociceptive and neuroprotective effects. The present study was designed to investigate the effect of curcumin on diabetic peripheral neuropathic pain and possible involvement of opioid system. A single dose of 60mg/kg streptozotocin was injected intraperitoneally to induce diabetes in rats. STZ-induced diabetic rats were treated with curcumin (50mg/kg/day) acute and chronically. Thermal hyperalgesia and mechanical allodynia were measured on the days 0, 7, 14 and 21 after diabetes induction as behavioral scores of neuropathic pain. Chronic, but not acute, treatment with curcumin prevents the weight loss and attenuates mechanical allodynia in STZ-induced diabetic rats. Pretreatment with naloxone (1mg/kg) significantly reduced anti-allodynic effect of chronic curcumin in von Frey filament test. Our results suggest that curcumin can be considered as a new therapeutic potential for the treatment of diabetic neuropathic pain and the activation of opioid system may be involved in the antinociceptive effect of curcumin.

Modulation of muscimol state-dependent memory by α2-adrenoceptors of the dorsal hippocampal area.

In the present study, the effects of bilateral intra-dorsal hippocampal (intra-CA1) injections of α2-adrenoceptor agonist and antagonist, on muscimol state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Administration of muscimol (0.1 µg/mouse, intra-CA1) 15 min before training or testing induced impairment of memory retention. Injection of the same dose of the drug 15 min before testing restored memory retention impaired under pre-training muscimol influence. Pre-test intra-CA1 administration of the α2-adrenoceptor agonist clonidine (0.5 and 1 µg/mouse) impaired memory retention, although the low dose of the drug (0.25 µg/mouse) did not affect memory retention. Pre-test intra-CA1 administration of the α2-adrenoceptor antagonist yohimbine (1 and 2 µg/mouse) improved memory retention, although the low dose of the drug (0.5 µg/mouse) did not affect memory retention. In other series of experiments, pre-test co-administration of certain doses of clonidine (0.125 and 0.25 µg/mouse, intra-CA1), doses which were ineffective when given alone, and muscimol (0.1 µg/mouse, intra-CA1) significantly inhibited muscimol state-dependent memory. Pre-test intra-CA1 administration of certain doses of yohimbine (0.25 and 0.5 µg/mouse), doses which were ineffective when given alone, improved pre-training muscimol (0.1 µg/mouse)-induced retrieval impairment. Moreover, pre-test co-administration of yohimbine (0.25 and 0.5 µg/mouse, intra-CA1) and muscimol (0.025 µg/mouse, intra-CA1), an ineffective dose, significantly restored the retrieval and induced muscimol state-dependent memory. It may be concluded that the α2-adrenoceptors of the dorsal hippocampal area play an important role in muscimol state-dependent memory.

Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system.

Lithium is a major drug for bipolar disorder and mania. Recently, many studies have shown the neuroprotective effect of lithium in different models of neurodegenerative diseases. The present study was carried out to examine the effect of lithium in a rat model of neuropathic pain induced by partial sciatic nerve ligation and the possible role of opioid system in this effect. To do so, animals received acute injection of saline, lithium (5, 10 and 15 mg/kg,) and naloxone (1 mg/kg) or the combination of naloxone (1 mg/kg) with lithium (10 mg/kg) intraperitoneally on the testing days. Thermal hyperalgesia, mechanical and cold allodynia were measured on the days 3, 5, 7, 10 and 14 after surgery. Lithium decreased thermal hyperalgesia scores with dose of 5, 10 and 15 mg/kg and cold and mechanical allodynia scores with dose of 10 and 15 mg/kg, significantly. The opioid antagonist naloxone prevented the effect of lithium on thermal hyperalgesia and mechanical allodynia while it did not show any effect on the acetone-induced cold allodynia. Our results suggest that lithium can be considered as a therapeutic potential for the treatment of some aspects of neuropathic pain and that the opioid system may be involved in the lithium-induced attenuation of thermal hyperalgesia and mechanical allodynia.

Cyclosporine attenuates the adenylyl cyclase superactivation induced by chronic cannabinoid treatment.

Chronic cannabinoid treatment results in the development of tolerance. Adenylyl cyclase superactivation, induced by chronic cannabinoid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present study, the effect of cyclosporine on adenylyl cyclase superactivation after chronic exposure to WIN 55,212-2, a cannabinoid receptor agonist, was studied. Chronic treatment (18 h) with WIN 55,212-2 induced a significant increase in cAMP levels in human astrocytoma cells (adenylyl cyclase superactivation). Acute treatment with cyclosporine (10 min) did not have any effect on WIN 55,212-2-induced adenylyl cyclase superactivation. But, chronic cyclosporine treatment (18 h), with concentration from 1 nM to 1 microM, attenuates the development of adenylyl cyclase superactivation after chronic WIN 55,212-2 treatment. Our findings show that cyclosporine attenuates chronic cannabinoid-mediated adenylyl cyclase superactivation.

The effect of cyclosporine on the development and expression of cannabinoid tolerance in mice.

Cyclosporine, beside its immunosuppressive action, has several effects on different neuronal functions, such as modulation of neurotransmitter release, the inhibition of nitric oxide synthesis and release, the reduction of cAMP production and inhibition of morphine-induced tolerance. In the present study, the effect of cyclosporine on the expression and development of tolerance to WIN 55,212-2, a cannabinoid receptor agonist, was studied. Intra peritoneal (i.p.) injection of WIN 55,212-2 (2-6 mg/kg) induced time-dependent and dose-dependent analgesia and catalepsy in mice. Administration of cyclosporine (20 mg/kg i.p.), 30 min before WIN 55,212-2 (6 mg/kg i.p.), did not change the analgesic and cataleptic effects of WIN 55,212-2. When WIN 55,212-2 (6 mg/kg i.p.) was injected once a day, animals became completely tolerant to the analgesic and cataleptic effects within five and nine days respectively. Cyclosporine (20 mg/kg i.p.) injected once daily, 30 min before WIN 55,212-2, attenuated the development of tolerance to the analgesic and cataleptic effects of WIN 55,212-2 but did not affect the expression of tolerance. Since cyclosporine given chronically by itself did not alter the analgesia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest cyclosporine may act with some selectivity on the mechanisms involved in development of cannabinoid tolerance.