The therapeutic role of minocycline in Parkinson's disease

Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease (PD), Huntington's disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD. © 2019 Cankaya S, Cankaya B, Kilic U, Kilic E, Yulug B. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission

Integrin alpha 5 beta 1 mediated cellular reorganization in human mesenchymal stem cells during neuronal differentiation

Background/Aim: Mesenchymal stem cells (MSCs) have been widely used for yielding neurons in culture to study nervous system pathologies and develop regenerative approaches. In this study, cellular rearrangements of human MSCs related to the expression of the fibronectin common receptor integrin alpha 5 beta 1 and its cell surface localization during neuronal differentiation, were examined. Materials and Methods: Proliferation kinetics of neuronal induced hMSCs (hMd-Neurons) were quantified by BrdU assay, and hMd-Neurons were immunostained for neuronal marker expression. Additionally, cDNA and protein samples were collected at different time points for integrin alpha 5 beta 1 expression analysis. Results: Endogenous integrin alpha 5 beta 1 expression was significantly upregulated by day 6 and maintained until day 12. Cell surface localization of alpha 5 beta 1 integrin was increased by day 6; the integrin was internalized into the cytosol by day 12. Conclusion: Integrin dynamics around day 6 of differentiation might be involved in neuronal differentiation and maturation or specification of hMd-Neurons.Istanbul Medipol University, Scientific Research Projects Committee (BAP

Two boron-containing compounds affect the cellular viability of SH-SY5Y cells in an in vitro amyloid-beta toxicity model

Boron is a naturally occurring trace element found in organic and inorganic complexes. Boron-containing compounds are required for living organisms for diverse metabolic functions, including nitrogen fixation in microorganisms, cell wall stability in plants, and bone and carbohydrate metabolism in animals. The number of studies about the effect of boron in biological model systems is very limited; so far, there has been no study on the correlation between boron and amyloid-beta toxicity. Here, we investigated the possible effects of 2 boron-containing compounds-sodium borate decahydrate and boric acid-against amyloid-beta toxicity. In our in vitro amyloid-beta toxicity model, we showed that these 2 compounds increase the survival of the SH-SY5Y cells. Furthermore, boron in these 2 forms increases the expression of Sirt1, which has protective functions against cellular stress. The compounds also change the expressions of GSK-3 alpha/beta; by doing so, boron may contribute to the stimulation of intracellular prosurvival pathways. This is the first experimental study indicating the prosurvival effect of boron in an amyloid-beta toxicity model

Effects of memantine and melatonin on signal transduction pathways vascular leakage and brain injury after focal cerebral ischemia in mice

WOS: 000317537800026PubMed ID: 23396088Because of their favorable action profiles in humans, both memantine and melatonin are particularly interesting candidates as neuroprotectants in acute ischemic stroke. Until now, the signaling mechanisms mediating memantine's neuroprotective actions remained essentially uninvestigated. In addition, we have combined memantine with melatonin, which is a well-known neuroprotective molecule. Herein, we examined the effects of memantine (20 mg/kg, i.p.) administered alone or in combination with melatonin (4 mg/kg, i.p.) on the activation of signaling transduction pathways, IgG extravasation and ischemic injury in mice submitted to 90 min of intraluminal middle cerebral artery occlusion, followed by 24 h of reperfusion. In these studies, both agents reduced ischemic injury and the density of DNA-fragmentation. Notably, melatonin/memantine combination reduced ischemic injury further as compared with memantine treatment, which was associated with reduced IgG extravasation, indicating vascular leakage in the brain. Animals receiving memantine exhibited elevated ERK-1/2 and decreased p21 and p38/MAPK activations, while it had no significant effect on phosphorylated Akt and SAPK/JNK1/2 in the ischemic brain. However, melatonin increased the activation of Akt and reduced the activations of ERK-1/2, p21, p38/MAPK and SAPK/JNK1/2 significantly. Synergistic effects of memantine and melatonin were observed in the inactivation of p21, p38/MAPK and SAPK/JNK1/2 pathways. Moreover, memantine reversed the effects of melatonin on the activation of ERK-1/2 pathway. Here, we provide evidence that free radical scavenger melatonin potentiates the effects of memantine on ischemic brain injury via inactivations of p21 and stress kinases p38/MAPK and SAPK/JNK1/2 pathways.EMBO (European Molecular Biology Organization); Turkish Academy of Sciences (TUBA/GEBIP)We thank M. Ugur and S. Eyuboglu for technical assistance. This work was supported by EMBO (European Molecular Biology Organization) installation Grant and The Turkish Academy of Sciences (TUBA/GEBIP)

Melatonin affects the release of exosomes and tau-content in in vitro amyloid-beta toxicity model

Background: Recent studies have been revealed that oxidative damage is the main cause of aging and age-related neurodegenerative diseases like Alzheimer's disease (AD). Melatonin is secreted from the pineal gland and its secretion has been found to be altered in AD. In the last decade the role of exosomes in spreading toxic proteins and inducing the propagation of diseases like AD has been discussed. However, it is not known how melatonin affects the amount of exosomes released from the cells and the content of the exosomes.Objective: Herein, we investigated the possible role of melatonin treatment in the releasing of exosomes and exosomal tau content in an in vitro A beta toxicity model.Method: SH-SY5Y cell line was used. The optimum concentration of A beta was determined by cell viability and cell proliferation tests. Melatonin (100 mM) was applied before and after A beta application. Total exosomes isolated from cell culture media were immunoprecipitated. The amount of released exosomes and their tau content were analyzed by Western blots.Results: Our data demonstrated for the first time that melatonin treatment clearly affected the amount of released exosomes. It would decrease the amyloid beta load and toxicity by inhibiting exosome release. We also demonstated that melatonin also affected the level of tau carried by exosomes depending on whether melatonin was applied before or after A beta application.Conclusion: It is considered that the effect of melatonin in the release of exosomes and exosomal tau content would contribute the development of therapeutic strategies in AD and related disorders

Therapeutic role of rifampicin in Alzheimer's disease

WOS: 000426795500003PubMed ID: 29315976Rifampicin exerts significant brain protective functions in multiple experimental models. Here we summarize the underlying mechanisms of the neuroprotective and pro-cognitive effects of rifampicin that are mediated by its anti-inflammatory, anti-tau, anti-amyloid, and cholinergic effects. Beyond suggesting that rifampicin shows strong brain protective effects in preclinical models of Alzheimer's disease, we also provide substantial clinical evidence for the neuroprotective and procognitive effects of rifampicin. Future neuroimaging studies combined with clinical assessment scores are the following steps to be taken in this field of research

Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

WOS: 000314541600001PubMed ID: 23311701Background: Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods: Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days), cisplatin treatment (7 mg/kg b.w., i.p.) and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N) and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-kappa B and AP-1 in Western blot analysis. Results: Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin treatment increased Nrf2 accumulation in the nuclear fraction, and increased the expression of HO-1 in the cytosolic fraction as compared to the cisplatin-treated rats. Expressions of NF-kappa B p65 and AP-1 were increased significantly in the kidneys of rats treated with cisplatin compared with the expression in the kidneys from the control, melatonin-only-treated and melatonin co-treated rats. Conclusion: Our present data suggest that melatonin attenuates cisplatin-induced nephrotoxicity possibly by modulating Nrf2/HO-1 signaling.EMBO (European Molecular Biology Organization) installation grant; Turkish Academy of Sciences (TUBA)This work was supported by EMBO (European Molecular Biology Organization) installation grant and The Turkish Academy of Sciences (TUBA)

The phosphatidylinositol-3 kinase/Akt pathway mediates melatonin's neuroprotective activity after focal cerebral ischemia

Joint Congress of European Neurology -- MAY 31-JUN 03, 2014 -- Istanbul, TURKEYWOS: 000337563601023European Journal of Neurology…European Federation of Neurological Societie

The phosphatidylinositol-3 kinase/Akt pathway mediates melatonin's neuroprotective activity after focal cerebral ischemia

Joint Congress of European Neurology -- MAY 31-JUN 03, 2014 -- Istanbul, TURKEYWOS: 000347674000755…European Federation of Neurological Societie

Effects of melatonin and memantine administration on the learning and memory performances of hypoxic juvenile rat pups

Objective: Herein, we aimed to investigate the long-term effects of neonatal hypoxia and the potential protective role of melatonin and memantine on the learning and memory. Methods: Seven-day-old rat underwent right carotid ligation, followed by hypoxia. Rat received Melatonin (MLT) (4 mg/kg), Memantine (MEM) (20 mg/kg), and MLT+MEM combination after hypoxia. We tested these rats for anxiety by elevated O-maze and for spatial learning and memory by Morris water maze (MWM) at postnatal day 45. Results: Hypoxia increased the level of anxiety compared to the control group (p=0.05) while treatment of MLT, MEM, and MLT+MEM ameliorated this effect. In addition, hypoxia produced significant decrease in spatial learning of the rats on the fourth day of training (P=0.05) and the percent time spent in the platform quadrant and the entrance frequencies to the platform quadrant compared to the control group (P=0.049 and P=0.023). Treatment of MLT, MEM, and MLT+MEM after hypoxia improved the performance of the rats at the third (P=0.686, P=0.876, P=0.977, respectively) and fourth day (P=0.738, P=0.553, P=0.789, respectively) of MWM training. The decrease in the percent time spent was ameliorated by the treatment of MLT (P=0.239), MEM (P=0.289), and MLT+MEM (P=0.567) compared to the control group. In addition, MLT treatment significantly increased the entrance frequency to the platform quadrant compared to the hypoxia group (P=0.020). Conclusion: Our data suggested that the MLT was more effective in the release of memory deficits from hypoxia-related damage. MLT might have a therapeutic value in improving hypoxic damage in the developing brain