The present study investigated the possible relationship between pro-inflammatory cytokines and programmed nigral neuronal death in rotenone model of Parkinson's disease (PD). Sitagliptin and liraglutide efficacy to inhibit the inflammatory-apoptotic degenerative process were investigated, too. The experimental PD were induced in male albino rats by ten subcutaneously injections of rotenone (3 mg/kg/day, s.c). All treatment drugs were administered for 16 days after induction of Parkinson rat's model. Sitagliptin and liraglutide were administered in three different dose levels (10-20-30 mg/kg, p.o), (25-50-100 μg/kg, s.c), respectively. Cylindrical and catalepsy tests were used to detect the optimum dose response of each drug. Sitagliptin (30 mg/kg/day, p.o) and liraglutide (50 μg/kg, s.c.) showed statistically significant (p ≤ 0.05) effect on behavioral activity. Where both doses improved the motor performance significantly in comparison with other doses in both cylindrical and catalepsy tests. Furthermore, they reversed rotenone-induced nigral neuronal loss, associated with marked decrease of pro-inflammatory cytokines: interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β1, together with a significant increase of striatal dopamine, nigral glial cell line-derived neurotrophic factor (GDNF), and tyrosine hydroxylase positive (TH+) cells. Moreover, the pro-apoptotic environment in nigrostriatal tissues was abrogated significantly, as the pro-apoptotic protein Bax decreased along with the anti-apoptotic protein Bcl-2 increased. In conclusion, sitagliptin and liraglutide represent a promising strategy to mitigate the progression of PD by their anti-inflammatory, anti-apoptotic neurotrophic and neurogenic mechanistic activities.
Epilepsy is a chronic widely prevalent neurologic disorder, affecting brain functions with a broad spectrum of deleterious consequences. High mobility group box1 (HMGB1) is a nuclear non‐histone protein that targets vital cell receptor of toll‐like receptor 4 (TLR4) and advanced glycation end products (RAGE). HMGB1 mediated TLR4/RAGE cascade has been scored as a key culprit in neuroinflammatory signalling that critically evokes development of impaired cognition and epilepsy. The current study aimed to investigate the neuroprotective effect of pentoxifylline (PTX) on pentylenetetrazol (PTZ)‐kindling rats by its anti‐inflammatory/antioxidant capacity and its impact on memory and cognition were investigated, too. PTZ was intraperitoneally injected 35 mg/kg, every 48 h, for 14 doses, to evoke kindling model. Phenytoin (30 mg/kg, i.p.) and PTX (60 mg/kg, i.p.) or their combination were given once daily for 27 days. PTX treatment showed a statistically significant effect on behavioural, histopathological and neurochemical analysis. PTX protected the PTZ kindling rats from epileptic seizures and improved memory and cognitive impairment through the Morris water maze (MWM) test. Furthermore, PTX reversed PTZ hippocampal neuronal loss by decreasing protein expression of amyloid‐β peptide (Aβ), Tau and β site‐amyloid precursor protein cleavage enzyme 1 (BACE1), associated with a marked reduction in expression of inflammatory mediators such as HMGB1, TL4, and RAGE proteins. Furthermore, PTX inhibited hippocampal apoptotic caspase 1 protein, total reactive oxygen species (TROS) along with upregulated erythroid 2‐related factor 2 (Nrf2) content. In conclusion, PTX or its combination with phenytoin represent a promising drug to inhibit the epilepsy progression via targeting the HMGB1/TLR4/RAGE signalling pathway.
Background and Purpose
Varicocele is a leading cause of male infertility. Melatonin is a highly pleiotropic neurohormone. We aimed to characterize the melatonin epigenetic potential in varicocele and the involved molecular mechanisms.
Experimental Approach
Fifty‐two male albino rats were randomly divided into four groups (13 rats each): control (I), melatonin (II), varicocele (III) and melatonin treated varicocele (IV) groups. Left varicocele was induced by partial left renal vein ligation. Reproductive hormones, epididymal sperm functional parameters, testicular 3/17 β‐hydroxysteroid dehydrogenases, antioxidant enzymes, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase, 8‐hydroxy‐2′‐deoxyguanosine and histopathological/Johnsen's score were evaluated. Flow cytometry and Comet were carried out to explore extent of sperm and testicular DNA damage. Testicular expression of silent information regulator 1 (SIRT1), forkhead transcription factors‐class O (type1) (FOXO1), tumour suppressor gene, P53, cation channels of sperm (CatSper) and steroidogenic acute regulatory protein was evaluated by western blot technique. Testicular expression of Bcl‐2 and its associated X protein and nuclear factor kappa‐light‐chain‐enhancer of activated B cells were assayed by immunohistochemical staining. Testicular miR‐34a expression was quantified by quantitative reverse transcription‐polymerase chain reaction.
Key Results
The varicocele induced testicular histological injury, enhanced oxidative stress, P53‐mediated apoptosis, DNA damage and increased testicular miR‐34a expression paralleled with down‐regulated SIRT1/FOXO axis. Melatonin treatment of varicocele rats displayed antioxidant/anti‐apoptotic efficacy and improved reproductive hormones axis, CatSper expression and fertility parameters. MiR‐34a/SIRT1/FOXO1 epigenetic axis integrates testicular melatonin mediated intracellular transduction cascades in varicocele.
Conclusion and Implications
Melatonin can be used as an adjuvant therapy to improve varicocele and its complication.
Parkinson’s
disease (PD) is the second most common neurodegenerative disease,
frequently associated with a gastric ulcer. We aimed to investigate
the adropin neuroprotective/gastroprotective potential in the indomethacin
(IND)-induced gastric ulcer in a rotenone-induced PD model. Rats were
randomly divided into four groups: normal control group, rotenone/IND
treated (PD /Ulcer) group, adropin treated PD/Ulcer group, and l-dopa/omeprazole (Om) treated PD/Ulcer group. There were ten
rats selected for the normal control group. Striatal dopamine (DA),
apoptosis/redox status, and motor/behavioral impairments were evaluated.
Gastric oxidative stress, H+/K+-ATPase activity,
prostaglandin E2, mucin content, and von Willebrand factor were measured.
Gastric/striatal phosphatidylinositol 3-kinase (PI3K)/phosphorylated
Akt and gastric vascular endothelial growth factor (VEGF)/striatal
P53 immunoreactivities were checked. Striatal P53 upregulated
modulator of apoptosis (Puma)/gastric
vascular endothelial growth factor receptor-2 (Vegfr-2) expressions were evaluated. Adropin successfully restored striatal
DA and attenuated rotenone-induced motor/behavior deficits along with
strong gastroprotective potential, possibly through antioxidant activity
via reduction in malondialdehyde level and upregulated superoxide
dismutase, catalase activities, and serum ferric reducing antioxidant
power. Adropin restored the delicate balance between the defective
pro-survival PI3K/Akt/murine double minute 2 signals and apoptotic
P53/Puma pathways. Adropin can be considered as a
uniquely attractive therapeutic target in PD and its associated gastric
ulcer.
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