Characterization of antinociceptive potency of endomorphin-2 derivatives with unnatural amino acids in rats

Kovács, Gy.; Petrovszki, Zita; Mallareddy, Jayapal Reddy; Tóth, Géza; Benedek, G.; Horváth, Gyöngyi

doi:10.1556/aphysiol.99.2012.3.12

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…For induction of osteoarthritis, rats were given a single intraarticular injection of 500 µg monosodium iodoacetate (MIA, Sigma-Aldrich Kft., Budapest, Hungary) in a volume of 50 μl through the infrapatellar ligament of the right hind knee using a 27-gauge needle 14,19 . Animals were left undisturbed for 14 days to develop mild cartilage destruction and osteoarthritis-like joint pain.…”

Section: Modeling Of Osteoarthritis and Cip Administrationmentioning

confidence: 99%

Neurobehavioral impairments in ciprofloxacin-treated osteoarthritic adult rats

Kékesi,

Ducza,

Gálity

et al. 2023

Ideggyógyászati szemle

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Background and purpose – Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinoloneinduced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition. Methods – Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex. Results – CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex. Conclusion – This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity.

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Section: Modeling Of Osteoarthritis and Cip Administrationmentioning

confidence: 99%

Neurobehavioral impairments in ciprofloxacin-treated osteoarthritic adult rats

Kékesi,

Ducza,

Gálity

et al. 2023

Ideggyógyászati szemle

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“…β‐Methylphenylalanine (C 10 H 13 NO 2 ) is a non‐proteogenic and non‐natural amino acid with a molecular weight of 179.216 Da. β‐Methylphenylalanine has been shown to exert an antinociceptive effect in experimental animals, 10 and Ren et al 11 demonstrated that β‐methylphenylalanine exhibited anti‐arthritic activity in male albino rats. However, limited research is available on the biological effects of β‐methylphenylalanine.…”

Section: Introductionmentioning

confidence: 99%

β‐Methylphenylalanine exerts neuroprotective effects in a Parkinson's disease model by protecting against tyrosine hydroxylase depletion

Yao

Yuan

2020

J Cellular Molecular Medi

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We evaluated the neuroprotective effects of β‐methylphenylalanine in an experimental model of rotenone‐induced Parkinson's disease (PD) in SH‐SY5Y cells and rats. Cells were pre‐treated with rotenone (2.5 µg/mL) for 24 hours followed by β‐methylphenylalanine (1, 10 and 100 mg/L) for 72 hours. Cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), mitochondrial fragmentation, apoptosis, and mRNA and protein levels of tyrosine hydroxylase were determined. In a rat model of PD, dopamine (DA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) levels, bradykinesia and tyrosine hydroxylase expression were determined. In rotenone–pre‐treated cells, β‐methylphenylalanine significantly increased cell viability and MMP, whereas ROS levels, apoptosis and fragmented mitochondria were reduced. β‐Methylphenylalanine significantly increased the mRNA and protein levels of tyrosine hydroxylase in SH‐SY5Y cells. In the rotenone‐induced rat model of PD, oral administration of β‐methylphenylalanine recovered DA and DOPAC levels and bradykinesia. β‐Methylphenylalanine significantly increased the protein expression of tyrosine hydroxylase in the striatum and substantia nigra of rats. In addition, in silico molecular docking confirmed binding between tyrosine hydroxylase and β‐methylphenylalanine. Our experimental results show neuroprotective effects of β‐methylphenylalanine via the recovery of mitochondrial damage and protection against the depletion of tyrosine hydroxylase. We propose that β‐methylphenylalanine may be useful in the treatment of PD.

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“…The radiolabelled GTP analogue, [ 35 with free access to food and water, and with a 12:12 h light/dark cycle. Animal suffering and the number of animals per group were kept at a minimum; therefore, the drugs were administered in cumulative doses in 30-min intervals (at 0th, 30th and 60th min), and injections were repeated 7 days apart for the same animal, as in our previous study [169].…”

Section: Radiochemicalsmentioning

confidence: 99%

“…These injections did not elicit signs of major distress. Within 14 days MIA had consistently been shown to cause severe end-stage cartilage destruction resulting in osteoarthritis-like joint pain accompanied with moderate edema [169,175,176]. The observer was blind to the drug treatment administered.…”

Section: Chronic Inflammatory Pain Model and Measuring Allodyniamentioning

confidence: 99%

Comparative biochemical and pharmacological investigations of various newly developed opioid receptor ligands

Szűcs¹

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Bentley analogues: In vitro competition binding experiments all derivatives showed low subnanomolar affinity to MOR. For DOR the ligands showed comparable binding affinities than the selective DOR agonist Ile5,6-deltorphin II peptide ligand except 8 (Ki > 3000 nM). In the KOR binding assays the analogues still displayed nanomolar affinities. In G-protein activity measurements compound 1f, 2a, 2b had antagonistic; 1e, 2c, 8 had partial agonistic and 2d, 4, 5, 7 had full agonistic effects. Ligands were examined in G-protein activation tests in rat brain membranes, the selectivity could not be observed as the receptor selective antagonists such as Cyp, NTI, nor-BNI and the selective agonists such as DAMGO, Ile5,6-deltorphine II, U-69,593 are not able to inhibit the effects of the extremely potent Bentley analogues. In vivo tests in osteoarthritis inflammatory model the thevinol derivatives showed a significant antiallodynic effect, while orvinol derivatives, except for 2c, did not display this effect. Oligopeptides: In competition binding assays the KYNA‐containing peptide, KA1 bound selectively to the MOR with a low Ki value and a high selectivity ratio, the other oligopeptides also showed selectivity to MOR, except K3, which bound to MOR and DOR with similar affinity. In the G-protein activition tests the EM-2 containing compounds, K2 and K3 stimulated G-protein with low efficacy, compound KA1, K4, K5 behaved as full agonists, while K6 had efficacy and potency higher than those of the reference compound DAMGO. In functional binding assays all oligopetides were inhibited by Cyp (MOR) and NTI (DOR) in rat brain membrane. In guinea pig brain membrane K4 and K6 stimulated G-protein, the efficacy of K4 was inhibited by nor-BNI, while the effect of K6 was not. K6 exhibited a strong antinociceptive effect in formalin test.

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Characterization of antinociceptive potency of endomorphin-2 derivatives with unnatural amino acids in rats

Cited by 9 publications

References 44 publications

Neurobehavioral impairments in ciprofloxacin-treated osteoarthritic adult rats

Neurobehavioral impairments in ciprofloxacin-treated osteoarthritic adult rats

β‐Methylphenylalanine exerts neuroprotective effects in a Parkinson's disease model by protecting against tyrosine hydroxylase depletion

Comparative biochemical and pharmacological investigations of various newly developed opioid receptor ligands

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