Pycnogenol ameliorates motor function and gene expressions of NF-ƙB and Nrf2 in a 6-hydroxydopamine-induced experimental model of Parkinson's disease in male NMRI mice.

We investigated the effect of Pycnogenol as an antioxidant on improving motor function, depression, and the expression of NF-ƙB and Nrf2 genes in the experimental model of Parkinson's disease. Forty adult male NMRI mice weighing about 30 g were randomly divided into five groups of eight. Saline group: received 3 µl of saline, as 6-hydroxydopamine (6-OHDA) solvent, unilaterally in the left striatum, treatment groups: first received 3 µl 6-OHDA unilaterally inside the ipsilateral striatum and then divided into subgroup A: received distilled water, Pycnogenol solvent, by gavage for 7 days (lesion group), and subgroup B: received Pycnogenol at doses of 10, 20, and 30 mg/kg by gavage for 7 days. Seven days after Parkinson's model induction, the apomorphine test, the degree of catalepsy by bar test, the duration of immobility (depression) by forced swimming test (FST) were measured. In addition, the expression of NF-ƙB and Nrf2 genes was measured using the real-time PCR technique. The total number of rotations in the apomorphine test decreased significantly in the groups receiving Pycnogenol. Administration of Pycnogenol significantly reduced catalepsy. The study of depression in the group receiving Pycnogenol showed a significant reduction. Also, Pycnogenol increased the expression of the Nrf2 anti-inflammatory gene, but it had no significant difference in the expression of NF-ƙB gene. Pycnogenol, presumably with its antioxidative and genomic effects, improves the expression of the anti-inflammatory gene and found that neuroprotection effect in the brain.

Complementary effects of coenzyme Q10 and Lepidium sativum supplementation on the reproductive function of mice: An experimental study.

BACKGROUND: Coenzyme Q10 (CoQ10) and Lepidium sativum (LS) have therapeutic effects on infertility. OBJECTIVE: To evaluate the combined effects of LS and CoQ10 on reproductive function in adult male NMRI mice. MATERIALS AND METHODS: Eighty three-months-old male mice (35-40 gr) were divided into four groups (n = 10/each): control (treated with water), CoQ10-treated (200, 300, and 400 mg/kg/body weight), LS-treated (200, 400, 600 mg/kg/body weight), and co-treated (LS [600 mg/kg/body weight] + CoQ10 [200 mg/kg/body weight]) groups. Serum testosterone, luteinizing hormone, follicle-stimulating hormone, and gonadotropin realizing hormone (GnRH) levels were measured using ELISA method. The sperm quality was assessed using Sperm Class AnalyzerⓇ (SCA) CASA system and GnRH mRNA expression levels were evaluated by real-time polymerase chain reaction. RESULTS: The number of sniffing and following behavior was significantly higher in LS-treated (400 and 600 mg/ml/body weight) groups than the control group (p = 0.0007 and p = 0.0010, respectively). The number of mounting and coupling behaviors was significantly higher in the CoQ10 (300 and 400 mg/ml/body weight)-treated animals than the control group (p = 0.0170 and p = 0.0006, respectively). Co-treatment of CoQ10 (200 mg/ml/body weight) and LS (600 mg/ml/body weight) significantly increased all aspects of sexual behaviors as well as the levels of serum testosterone (p = 0.0011), luteinizing hormone (p = 0.0062), and follicle-stimulating hormone (p = 0.0001); sperm viability (p = 0.0300) and motility (p = 0.0010); and GnRH mRNA levels (p = 0.0016) compared to the control group. CONCLUSION: The coadministration of CoQ10 and LS significantly improves the activity of the hypothalamic-pituitary-gonadal axis and enhances the reproductive parameters in adult male mice.

Effects of intrathecal and intracerebroventricular microinjection of kaempferol on pain: possible mechanisms of action.

BACKGROUND AND PURPOSE: Kaempferol (KM), a flavonoid, has an anti-inflammatory and anticancer effect and prevents many metabolic diseases. Nonetheless, very few studies have been done on the antinociceptive effects of KM. This research aimed at assessing the involvement of opioids, gamma-aminobutyric acid (GABA) receptors, and inflammatory mediators in the antinociceptive effects of KM in male Wistar rats. EXPERIMENTAL APPROACH: The intracerebroventricular and/or intrathecal administration of the compounds was done for examining their central impacts on the thermal and chemical pain by the tail-flick and formalin paw tests. For assessing the role of opioid and GABA receptors in the possible antinociceptive effects of KM, several antagonists were used. Also, a rotarod test was carried out for assessing motor performance. FINDINGS/RESULTS: The intracerebroventricular and/or intrathecal microinjections of KM (40 µg/rat) had partially antinociceptive effects in the tail-flick test in rats (P < 0.05). In the formalin paw model, the intrathecal microinjection of KM had antinociceptive effects in phase 1 (20 and 40 µg/rat; P < 0.05 and P < 0.01, respectively) and phase 2 (20 and 40 µg/rat; P < 0.01 and P < 0.001, respectively). Using naloxonazine and/or bicuculline approved the involvement of opioid and GABA receptors in the central antinociceptive effects of KM, respectively. Moreover, KM reduced the expression levels of caspase 6, interleukin-1ß, tumor necrosis factor-α, and interleukin-6. The antinociceptive effects of KM were not linked to variations in the locomotor activity. CONCLUSION AND IMPLICATIONS: It can be concluded that KM has remarkable antinociceptive effects at a spinal level, which is associated with the presence of the inflammatory state. These impacts were undetectable following injections in the lateral ventricle. The possible mechanisms of KM antinociception are possibly linked to various modulatory pathways, including opioid and GABA receptors.

Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response.

OBJECTIVES: There has been increasing evidence that the γ-aminobutyric acid (GABA)ergic system is involved in the neurobiology of anxiety. The present study aimed to investigate the role of GABAergic systems in the modulation of anxiety in the medial prefrontal cortex (mPFC) of rats using the elevated plus maze test. METHODS: Rats were anaesthetised with a mixture of ketamine and xylazine, and then special cannulae were inserted stereotaxically into the mPFC. After 5-7 days of recovery, the effects of intra-mPFC administration of GABAergic agents were studied. RESULTS: Bilateral injection of the GABAA receptor agonist muscimol (0.25, 0.5 and 1 µg/rat) produces an anxiolytic-like effect, shown by significant increases in the percentage of open-arm time (%OAT) and percentage of open-arm entries (%OAE). Intra-mPFC administration of the GABAA receptor antagonist bicuculline (0.25, 0.5 and 1 µg/rat) produces significant anxiogenic-like behaviour. However, intra-mPFC injection of the GABAB receptor agonist baclofen (0.05, 0.1 and 0.2 µg/rat) and the GABAB receptor antagonist CGP35348 (5, 10 and 15 µg/rat) did not alter %OAT and %OAE significantly. CONCLUSION: The results of the present study demonstrate that the GABAergic system of the mPFC modulates anxiety-related behaviours of rats through GABAA receptors.

Effect of phencyclidine derivatives on anxiety-like behavior using an elevated-plus maze test in mice.

OBJECTIVES: The study attempted to investigate the anti-anxiety activities of Phencyclidine (1-(1-phenylcyclohexyl) piperidine, PCP, I) and some of its derivatives (M, F, L, B, S, P) with the elevated-plus maze (EPM) Test. MATERIAL AND METHODS: Phencyclidine and its derivatives (M, F, L, B, S, P) were administrated intraperitoneally (i.p.) at a dose of 10 mg/kg to male mice. Anxiety-like behaviors were assessed using the elevated-plus maze test. RESULTS: EPM results revealed an increase in open arms time spent after applying PCP and M, L, P, and B compounds at the administered dosage. Moreover, an increase in the number of open arm entries was observed with M, P, and B compounds. The P, B and S compounds increased the locomotion of animals, too, which might be considered as the side effect to the compounds. CONCLUSIONS: Considering the elevated-plus maze results, it was concluded that M and L compounds could be considered as a potential anxiolytic with less side effects due to a probable high electron donation of the methoxy group, as well as the hydrophilic properties of hydroxyl groups on these compounds.

Synthesis and study the analgesic effects of new analogues of ketamine on female wistar rats.

Ketamine (2-o-chlorophenyl-2-methylaminocyclohexan, CAS 1867-66-9, CI-581, Ketalar, I), a potent derivative of Phencyclidine (1-[1-phenylcyclohexyl] piperidine, CAS 956-90-1, PCP, II), and many of its analogues have shown anesthetic and analgesic effects. In this research, new derivatives of I, (2-[p-methoxybenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-OCH3, III), (2-[p-methylbenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-CH3, IV) and their intermediates (V-VIIII) were synthesized and the acute and chronic pains of III and IV were evaluated on rats using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests. The results werecompared with ketamine and control (saline) groups. The results indicated that in tail immersion and formalin tests, these new derivatives (III and IV) were usually effective for decreasing pain on rats.

Effects of prenatal lipopolysaccharide exposure on reproductive activities and serum concentrations of pituitary-gonadal hormones in mice offspring.

BACKGROUND: Maternal infection during pregnancy is a risk factor for some behavioral problems with neurodevelopmental origin. This study aimed to evaluate the effects of exposure of pregnant mice to the bacterial lipopolysaccharide (LPS) on sexual behaviour and serum level of pituitary-gonadal hormones of offspring in adulthood. MATERIALS AND METHODS: In this Expremental study, pregnant NMRI mice (n=7/group) were treated with intra-peritoneal administration of LPS (1, 5 and 10 µg/kg) at day 10 of gestation. Induction of the pro-inflammatory cytokines, Tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) were measured in maternal serum 2 hours following the maternal LPS challenge. Behavior in the adult male offspring reproductive activity was investigated using receptive female mice. Concentrations of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in adult offspring serum were measured using the enzyme-linked immunosorbent assay (ELISA) method (at postnatal day 60, n=10/group). RESULTS: One-way ANOVA showed that LPS administration induces a significant increase in TNF-α, IL-1ß and IL-6 levels of maternal serum. Prenatal LPS exposure reduces sexual behavior and serum concentration of LH and testosterone in adult male offspring. CONCLUSION: The overall results suggest that prenatal exposure to LPS increases pro- inflammatory cytokine levels, affects development of neuroendocrine systems and results in the inhibition of reproductive behaviors and reactivity of hypothalamic-pituitary-gonadal (HPG) axis in adult male offspring.

Intraocular pressure and Schirmer tear test results in clinically normal Long-Eared Hedgehogs (Hemiechinus auritus): reference values.

OBJECTIVE: The present study was undertaken to establish reference values for Schirmer tear test (STT) and intraocular pressure (IOP) in the long-eared hedgehog (Hemiechinus auritus). ANIMALS: Fourteen healthy long-eared hedgehogs (H. auritus) of either sex were studied. PROCEDURES: The hedgehogs were individually immobilized with an intramuscular injection of combined Ketamine (20 mg/kg) and Diazepam (0.5 mg/kg), and each animal underwent ophthalmic examinations including: STT, tonometry, biomicroscopy, and indirect ophthalmoscopy. RESULTS: No significant effects of animal gender, weight, side (right vs. left eye) were found in this study. Mean (SD) STT values for all eyes (n = 28) were 1.7 ± 1.2 mm/1 min with a range of 0-4 mm/1 min. Mean STT in male animals was 2.2 ± 1.2. Mean STT in female Hedgehogs was 1.3 ± 1.1. Mean (SD) IOP values by applanation tonometry were 20.1 ± 4.0 mmHg (range 11.5-26.5 mmHg). Mean (SD) IOP values by applanation tonometry were 18.2 ± 4.0 and 22.0 ± 3.2 mmHg for males and females, respectively. CONCLUSIONS: This study reports STT and IOP findings in long-eared hedgehogs (H. auritus).

Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP, I) and many of its analogues have shown some pharmacological effects. In this study, new pyrrole derivatives of I (1-(1-phenylcyclohexyl)pyrrole, II and 1-[1-(4-methylphenyl)(cyclohexyl)]pyrrole, III) and their intermediates were synthesized and the acute and chronic pains were examined on mice using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests and the results were compared with the PCP and control groups. The results indicated that III generated higher analgesic effects in the tail immersion test compared to the PCP and control (dimethyl sulfoxide, DMSO) groups, demonstrating a marked and significant increase in tail immersion latency, but this effect was not observed for II in the dose of 1 mg/kg. The formalin test showed that III was effective in acute chemical pain (phase I, 0-5 min after injection), but was not effective for II at the same dosage compared to the PCP and control groups. Also chronic pain will be significantly attenuated by III but II was not effective as compared to the other groups. It is concluded that substitution of the aromatic pyrrole ring instead of piperidine in the PCP molecule will not be effective alone in tail immersion and formalin tests but the addition of a methyl group (with high electron donating and dipole moments) on the phenyl group plus substitution of the aromatic pyrrole ring can be effective in acute and chronic pain compared to the PCP and control groups.

Synthesis and determination of acute and chronic pain activities of 1-[1-(4-methylphenyl) (cyclohexyl)] morpholine as a new phencyclidine derivative in rats.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 77-10-1, PCP, I) and many of its analogues have been synthesized and their pharmacological properties studied. In this research, new methyl morpholine derivative of phencyclidine (1-[1-(4-methylphenyl) (cyclohexyl)]morpholine, Methyl-PCM, III) was synthesized and the acute and chronic pain activities were studied using tail immersion and formalin tests on rats and compared to PCP and PCM (1-(1-phenylcyclohexyl)morpholine, CAS 2201-40-3, PCP-morpholine, II). The results Indicated that Methyl-PCM (III, 6 mg/kg, i.p) produces more analgesic effects in tail immersion test (as a model of acute thermal pain) in comparison with the PCP, PCM and control groups. Meanwhile, this analgesic effect was markedly shown 5-15 min after the compound III application. In formalin test analysis, the acute pain (phase I) could not be affected by any drugs, but the chronic formalin pain (phase II) could be diminished by PCM and especially compound III. The chronic analgesic effect of Methyl-PCM was markedly shown in the late phase of chronic pain.

New morpholine analogues of phencyclidine: chemical synthesis and pain perception in rats.

Phencyclidine (PCP, I) and most its derivatives have demonstrated some pharmacological effects. Accordingly, in this study, the new methoxy (III) and hydroxy-methyl (IV) morpholine PCP derivatives were synthesized. The acute and chronic pain activities of these drugs (III, IV) were investigated by tail immersion and formalin tests on rats and the results were compared with those in PCP, PCM (PCP-morpholine, II), and methyl-PCM (V). Findings indicated that III (6 mg/kg, i.p.) generates more analgesic effects in tail immersion test in comparison with I and II in 20, 40, 45 and 55 min post-injection. These effects were observed in 10, 20, 40, 45 and 50 min after the application of IV (at the same dosage). This analgesic effect was markedly seen in 20, 40, 45 and 50 min after compound IV's application in comparison with the drugs (I-V). In formalin test analysis, the acute chemical pain (Phase I) could not be affected by any drugs (I-V) while chronic formalin pain would be diminished by these new synthesized drugs (III and IV), especially in late Phase II, compared to I and II at the dosage of 6 mg/kg. It is, therefore, concluded that these new synthesized PCP derivates including methoxy-PCM (III) and hydroxy-methyl-PCM (IV) could substantially and respectively diminish acute thermal and chronic chemical pains.

Synthesis and analgesic effects of 1-[1-(2-methylphenyl)(cyclohexyl)]-3-piperidinol as a new derivative of phencyclidine in mice.

Phencyclidine (1-(1-phenylcyclohexyl) piperidine, CAS 956-90-1, PCP, I) and its derivatives have shown many analgesic effects. In this research, a new derivative of PCP (1-[1-(2-methylphenyl) (cyclohexyl)l3-piperidinol, PD, II) was synthesized and its analgesic (acute and chronic pains) effects were examined on rats using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests and the results are compared to PCP and control groups. The results indicated that II produces higher analgesic effects in the tail immersion test compared to the PCP and control groups, with a marked and significant increase in tail immersion latency for the doses 1, 5 and 10 mg/kg. The formalin test showed that PD (II) is not effective in acute chemical pain (phase I, 0-5 min after injection) in all doses but chronic pain (initial-phase II, 15-40 min after injection) is significantly attenuated by this compound compared to PCP and saline (control) in dosesof 5 and 10 mg/kg. It is concluded that II is effective in acute thermal (in all doses) and chronic (doses of 5 and 10 mg/kg) pains; however, it is not effective in acute chemical pain compared to PCP and control.

Synthesis and determination of chronic and acute thermal and chemical pain activities of a new derivative of phencyclidine in rats.

Phencyclidine (1-(1-phenylcyclohexyl) piperidine, PCP, I) and ketamine (2-O-chlorophenyl-2-methylaminocyclohexan, II) have shown analgesic effects. Some of its derivatives were synthesized and their biological properties have been studied. In this study, a new derivative of PCP, (1-[1-(3-methoxyphenyl) (tetralyl)] piperidine, PCP-OCH3-tetralyl, III) was synthesized and the acute thermal pain of this compound was determined using tail immersion test on rats and the results were compared with Ketamine and PCP. The results indicated a marked anti-nociception 2-25 min after ketamine injection, but the analgesic effect remained for 40 min following PCP-OCH3-tetralyl application in tail immersion test. However, the data obtained from formalin test showed that the chronic anti-nociception effect of ketamine was higher than PCP and PCP-OCH3-tetralyl exhibited almost similar analgesic effect.

Synthesis and study on analgesic effects of 1-[1-(4-methylphenyl) (cyclohexyl)] 4-piperidinol and 1-[1-(4-methoxyphenyl) (cyclohexyl)] 4-piperidinol as two new phencyclidine derivatives.

Phencyclidine (1-(1-phenylcyclohexyl) piperidine; CAS 956-90-1; PCP, I) has shown analgesic effects. Some of its derivatives have been synthesized and their biological properties have been studied. In this work, new methyl and methoxy hydroxyl derivatives of phencyclidine were synthesized and the analgesic effects of this compounds [(1-[1-(4-methylphenyl) (cyclohexyl)] 4-piperidinol, II), (1-[1-(4-methoxyphenyl) (cyclohexyl)] 4-piperidinol, III)] were studied using tail immersion test on rats and compared to PCP. The results showed that, II can produce more analgesic effects in the tail immersion test (as a model of acute thermal pain) in comparison to the PCP with a marked significant increase in tail immersion latency (15, 40 and 45 min after injection) but for III, only slight analgesic effects (15, 35 and 40 min after injection) was seen (without significant differences between pain thresholds).