DP. Benefi cial eff ect of chronic treatment with extracts from Rhodiola rosea L. and Curcuma longa L. on the immunoreactivity of animals subjected to a chronic mild stress model. Folia Medica 2017;59(4): 443-53. doi: 10.1515/folmed-2017-0046 Background: Recent studies have suggested increased levels of pro-infl ammatory cytokines in depression. Aim: The present study aimed to evaluate the eff ect of extracts from Rhodiola and Curcuma on immunoreactivity of animals subjected to a chronic mild stress (CMS) model followed by lipopolysaccharide-induced infl ammation. Materials and methods: Male Wistar rats (n=56) divided in 7 groups were treated orally with: distilled water 10 ml/kg (control and CMS model groups); Rhodiola 250 mg/kg; Rhodiola 500 mg/kg; Curcuma 250 mg/kg; Curcuma 500 mg/kg, Rhodiola 250 mg/kg and Curcuma 250 mg/kg. All groups except the control were stressed daily according to a CMS protocol. Changes in glucose preference, weight gain and locomotor activity were recorded. In the sixth week the animals were challenged with LPS and rats' sera were obtained for ELISA evaluation of TNF-α and IL-6 levels. Results:The animals from the model group decreased their weight gain, glucose preference and locomotor activity compared to controls. The groups exposed to stress and treated with Rhodiola 500 mg/kg, Curcuma 500 mg/kg and their combination increased their locomotor activity compared to the model group. High expression of the pro-infl ammatory cytokines TNF-α and IL-6 were found in all groups exposed to CMS and challenged by LPS. Conclusions: The groups exposed to the stress procedure showed a variety of depression-like behavioral changes. In addition, ELISA tests showed that CMS is aff ecting rats' immunity by increasing the cytokines' levels. These changes could be reversed by administration of Rhodiola and Curcuma in combination suggesting synergic interaction regarding their anti-infl ammatory and anti-stress eff ects. BACKGROUND

Deregulated cytokines' production is found in depressed patients. Salidroside and curcumin both have been described with potential antidepressant-like activities. The present study investigated the effect of pure salidroside, curcumin and their combination on the immunoreactivity of animals, subjected to a chronic mild stress (CMS) model, followed by lipopolysaccharide (LPS)-induced inflammation. Wistar male rats were separated in the following six groups: control, CMS model, fluoxetine (2.5 mg/kg, oral), salidroside (5 mg/kg, oral), curcumin (20 mg/kg, oral) and salidroside + curcumin (5 mg/kg + 20 mg/kg, oral). Changes in glucose preference, spatial learning and exploratory behavior were recorded. The IL-6 levels in the rats' sera and of the TNF-α levels in the rats' sera and the brain tissue homogenate were evaluated. The groups exposed to stress and treated with fluoxetine, salidroside, curcumin or salidroside + curcumin showed increase in the glucose preference and locomotor activity, as well as, decrease in the escape latency and the cytokines' levels compared to the CMS model group. The chronic stress induced behavioral alternations and increased cytokines' levels in rats which were reversed by administration of salidroside and curcumin, suggesting antidepressant-like effects comparable to that of fluoxetine and potential synergistic interaction regarding the anti-inflammatory and anti-stress effects.

The interplay of chronic stress, neuroinflammation and altered immune reactivity has been shown to be important for the pathophysiology of brain disorders such as schizophrenia, depressive disorders and post-traumatic stress disorder. This immuno-inflammatory theory has been extensively studied in the past three decades leading to the formation of the integrative discipline of psychoneuroimmunology. Targeting of the central nervous system by conventional pharmacotherapeutic methods is mainly through modulation of neuroendocrine systems such as the dopaminergic, GABA-ergic, adrenergic and serotoninergic systems. In recent years an increasing number of both experimental and clinical studies have shown that antidepressants can affect the immune system by reducing the production of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. However, due to the serious adverse effects accompanying the chronic administration of psychoactive drugs there is a continuous need to produce novel therapeutics that are both potent and safe. The present review aims to summarize the current knowledge in the field of psychoneuroimmunology and to delineate the main interactions between stress, inflammation, immunity and the brain. Additionally, this paper explores the use of plant-derived molecules that display a strong anti-stress effect and simultaneously modulate the immune response as an alternative or adjuvant to classical antidepressant drugs.

Background. Glutamate N-methyl-D-aspartate (NMDA) receptors are known for their importance in the perseverance of chronic neuropathic pain. Ketamine, an intravenous anesthetic agent, is a non-competitive blocker of NMDA receptors. Applied in anesthetic doses, ketamine has anti-nociceptive effects in various animal pain models. Objectives. The objective of this study was to investigate the anti-nociceptive effect of ketamine in acute and neuropathic pain models in rats. Material and methods. To study the anti-nociceptive effect of ketamine on acute pain, 40 Wistar rats were divided into 5 groups (n = 8): control, positive control group and 3 experimental groups treated intraperitoneally (ip.) with 30 mg/kg bw, 40 mg/kg bw and 50 mg/kg bw ketamine, respectively. The anti-nociceptive effect was evaluated in hot plate, analgesy-meter and formalin tests. The model of neuropathic pain was induced by left sciatic nerve ligation. Twenty-four Wistar rats were divided into 3 groups (n = 8): sham-control group, model group and ketamine-treated group subsequently tested in hot plate and analgesy-meter tests. Results. In the hot plate test, the rats treated with ketamine presented increased reaction latency at the 120 th min and 180 th min compared to the controls. In the analgesy-meter test, ketamine produced an antinociceptive effect at the 60 th min compared to the controls. In the formalin test, the paw licking time across the early phase of testing was reduced in the rats treated with the 2 higher doses of ketamine. In a neuropathic pain model, ketamine increased the reaction latency at the 120 th min and 180 th min compared with the model group in the hot plate test. In the analgesy-meter test, in the ketamine-treated animals the paw withdrawal threshold increased at the 60 th min compared with the model group. Conclusions. Our results suggest that ketamine produces peripheral anti-nociceptive effect in an acute pain model. Also, it relieves thermal and mechanical allodynia after 14 days of treatment in a neuropathic pain model.

The effects of 3R,16S-2-hydroxyethyl apovincaminate (HEAPO, RGH-10885) compared with those of two cholinesterase inhibitors, donepezil and galantamine, were examined in naïve Wistar rats using standard active and passive avoidance tests. The active avoidance test (shuttle box) and two passive avoidance tests (step-through and step-down) were performed according to the experimental design. There were 10 groups of rats (n = 8) and the substances studied were applied orally before each testing session. In the active avoidance test, the number of conditioned stimuli (avoidances), unconditioned stimuli (escapes) and intertrial crossings were observed. In step-down and step-through passive avoidance tests, the latencies of reactions were observed. All the studied compounds showed positive effects in the learning and memory tests, compared to the controls. It was concluded that HEAPO, donepezil and galantamine had a memory-enhancing effect in active and passive avoidance tests.