Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach

Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin \u3c Gemcitabine \u3c Topotecan \u3c Doxorubicin \u3c Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC. View Full-Tex

The role of GABA, glycine, nicotinic, and adrenergic receptors in developing central white matter ischaemic injury and the features of NG2 expressing cells in this tissue

Prolonged perinatal ischaemia is an important factor in the development of periventricular leukomalacia (PVL), which is the most common white matter pathology associated with cerebral palsy (CP): approximately 1.5 to 2.5 per 1,000 live births per year suffer from CP. During central nervous system (CNS) ischaemia, there is an excessive accumulation of extracellular neurotransmitters. Ischaemia affects axons and glial cells of white matter, which occupy approximately 50% of the human brain. The mechanisms of ischaemic-induced injury in astrocytes vary at different ages. Ischaemic injury in postnatal day 0 (P0) of rat optic nerve (RON) astrocytes is Ca[superscript 2+]-dependent and mediated by voltage-gated Ca[superscript 2+] channels (VGCCs). Astrocytes are replete with neurotransmitter receptors. Using an ex vivo model of ischaemia (oxygen-glucose deprivation: OGD) and Ca[superscript 2+] imaging, I investigated the role of gamma-aminobutyric acid (GABA), glycine, nicotine and norepinephrine in P0 RON during ischaemia. OGD produced a rapid and significant increase in cell death. A GABA antagonist (picrotoxin), a glycine antagonist (strychnine) and their combination protected P0 RON astrocytes from ischaemic injury. They reduced the total percentage of cell death and postponed the initial cell death. Immunohistochemistry revealed that GABA and glycine receptors are expressed by astrocytes and axons in P0 RON. On the other hand, blocking nicotinic acetylcholine receptors (nAChRs: mecamylamine or α-bungarotoxin) or blocking adrenergic receptors (combination of propranolol and phentolamine) had no effect. Using a glial injury scoring system, ultrastructural studies confirmed the protective action of picrotoxin and strychnine against ischaemia, which cannot be achieved by mecamylamine or a combination of propranolol and phentolamine. Chondroitin sulphate proteoglycans (NG2) (+) cells are a distinct type of glial cell which, over time, have come to be known as the fourth type of glia. These cells are distributed throughout the developing and adult CNS, and are known to be mitotically active even in the adult CNS. The astrocyte fate of NG2 (+) cells is a matter of debate. In the current study, the focus was on studying the morphological features of NG2 (+) cells at the ultrastructural level and under confocal microscope, and more precisely their relation to astrocytes in nRON following post-embedding immunolabelling. Immuno-electron microscope (I-EM) revealed NG2 immunoreactivity in nRON astrocytes. Double immunolabelling showed an overlap between NG2 (+) and (glial fibrillary acidic protein) GFAP (+) populations in nRON, adult RON and cortical grey matter

The role of GABA, glycine, nicotinic, and adrenergic receptors in developing central white matter ischaemic injury and the features of NG2 expressing cells in this tissue

Prolonged perinatal ischaemia is an important factor in the development of periventricular leukomalacia (PVL), which is the most common white matter pathology associated with cerebral palsy (CP): approximately 1.5 to 2.5 per 1,000 live births per year suffer from CP. During central nervous system (CNS) ischaemia, there is an excessive accumulation of extracellular neurotransmitters. Ischaemia affects axons and glial cells of white matter, which occupy approximately 50% of the human brain. The mechanisms of ischaemic-induced injury in astrocytes vary at different ages. Ischaemic injury in postnatal day 0 (P0) of rat optic nerve (RON) astrocytes is Ca[superscript 2+]-dependent and mediated by voltage-gated Ca[superscript 2+] channels (VGCCs). Astrocytes are replete with neurotransmitter receptors. Using an ex vivo model of ischaemia (oxygen-glucose deprivation: OGD) and Ca[superscript 2+] imaging, I investigated the role of gamma-aminobutyric acid (GABA), glycine, nicotine and norepinephrine in P0 RON during ischaemia. OGD produced a rapid and significant increase in cell death. A GABA antagonist (picrotoxin), a glycine antagonist (strychnine) and their combination protected P0 RON astrocytes from ischaemic injury. They reduced the total percentage of cell death and postponed the initial cell death. Immunohistochemistry revealed that GABA and glycine receptors are expressed by astrocytes and axons in P0 RON. On the other hand, blocking nicotinic acetylcholine receptors (nAChRs: mecamylamine or α-bungarotoxin) or blocking adrenergic receptors (combination of propranolol and phentolamine) had no effect. Using a glial injury scoring system, ultrastructural studies confirmed the protective action of picrotoxin and strychnine against ischaemia, which cannot be achieved by mecamylamine or a combination of propranolol and phentolamine. Chondroitin sulphate proteoglycans (NG2) (+) cells are a distinct type of glial cell which, over time, have come to be known as the fourth type of glia. These cells are distributed throughout the developing and adult CNS, and are known to be mitotically active even in the adult CNS. The astrocyte fate of NG2 (+) cells is a matter of debate. In the current study, the focus was on studying the morphological features of NG2 (+) cells at the ultrastructural level and under confocal microscope, and more precisely their relation to astrocytes in nRON following post-embedding immunolabelling. Immuno-electron microscope (I-EM) revealed NG2 immunoreactivity in nRON astrocytes. Double immunolabelling showed an overlap between NG2 (+) and (glial fibrillary acidic protein) GFAP (+) populations in nRON, adult RON and cortical grey matter.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effects of Different Lipopolysaccharide Doses on Short- and Long-Term Spatial Memory and Hippocampus Morphology in an Experimental Alzheimer’s Disease Model

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Various animal models are widely used to investigate its underlying mechanisms, including lipopolysaccharide (LPS)-induced neuroinflammation models. Aim: In this study, we aimed to investigate the effect of different doses (0.25, 0.5, and 0.75 mg/kg) of LPS on short- and long-term spatial memory and hippocampal morphology in an experimental AD mouse model. Materials and methods: Twenty-four adult male Swiss mice (SWR/J) weighing 18–25 g were divided into four groups: control, 0.25 mg/kg LPS, 0.50 mg/kg LPS, and 0.75 mg/kg LPS. All groups were treated with LPS or vehicle for 7 days. Behavioral tests were started (Morris water maze for 6 days and Y maze for 1 day) on the last 2 days of injections. After the behavioral procedures, tissues were collected for further histological investigations. Result: All LPS doses induced significant short- and long-term spatial memory impairment in both the Y maze and Morris water maze compared with the control group. Furthermore, histological examination of the hippocampus indicated degenerating neurons in both the 0.50 mg/kg and 0.75 mg/kg LPS groups, while the 0.25 mg/kg LPS group showed less degeneration. Conclusion: our results showed that 0.75 mg/kg LPS had a greater impact on early-stage spatial learning memory and short-term memory than other doses. Our behavioral and histological findings suggest 0.75 mg/kg LPS as a promising dose for LPS-induced AD models

Effects of Different Lipopolysaccharide Doses on Short- and Long-Term Spatial Memory and Hippocampus Morphology in an Experimental Alzheimer’s Disease Model

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Various animal models are widely used to investigate its underlying mechanisms, including lipopolysaccharide (LPS)-induced neuroinflammation models. Aim: In this study, we aimed to investigate the effect of different doses (0.25, 0.5, and 0.75 mg/kg) of LPS on short- and long-term spatial memory and hippocampal morphology in an experimental AD mouse model. Materials and methods: Twenty-four adult male Swiss mice (SWR/J) weighing 18–25 g were divided into four groups: control, 0.25 mg/kg LPS, 0.50 mg/kg LPS, and 0.75 mg/kg LPS. All groups were treated with LPS or vehicle for 7 days. Behavioral tests were started (Morris water maze for 6 days and Y maze for 1 day) on the last 2 days of injections. After the behavioral procedures, tissues were collected for further histological investigations. Result: All LPS doses induced significant short- and long-term spatial memory impairment in both the Y maze and Morris water maze compared with the control group. Furthermore, histological examination of the hippocampus indicated degenerating neurons in both the 0.50 mg/kg and 0.75 mg/kg LPS groups, while the 0.25 mg/kg LPS group showed less degeneration. Conclusion: our results showed that 0.75 mg/kg LPS had a greater impact on early-stage spatial learning memory and short-term memory than other doses. Our behavioral and histological findings suggest 0.75 mg/kg LPS as a promising dose for LPS-induced AD models

Biochanin A Improves Memory Decline and Brain Pathology in Cuprizone-Induced Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by the demyelination of nerves, neural degeneration, and axonal loss. Cognitive impairment, including memory decline, is a significant feature in MS affecting up to 70% of patients. Thereby, it substantially impacts patients’ quality of life. Biochanin A (BCA) is an o-methylated isoflavone with a wide variety of pharmacological activities, including antioxidant, anti-inflammatory, and neuroprotective activities. Thus, this study aimed to investigate the possible protective effects of BCA on memory decline in the cuprizone (CPZ) model of MS. Thirty Swiss albino male mice (SWR/J) were randomly divided into three groups (n = 10): control (normal chow + i.p. 1:9 mixture of DMSO and PBS), CPZ (0.2% w/w of CPZ mixed into chow + i.p. 1:9 mixture of DMSO and PBS), and CPZ + BCA (0.2% w/w of CPZ mixed into chow + i.p. 40 mg/kg of BCA). At the last week of the study (week 5), a series of behavioral tasks were performed. A grip strength test was performed to assess muscle weakness while Y-maze, novel object recognition task (NORT), and novel arm discrimination task (NADT) were performed to assess memory. Additionally, histological examination of the hippocampus and the prefrontal cortex (PFC) were conducted. BCA administration caused a significant increase in the grip strength compared with the CPZ group. Additionally, BCA significantly improved the mice’s spatial memory in the Y-maze and recognition memory in the NORT and the NADT compared with the CPZ group. Moreover, BCA mitigated neuronal damage in the PFC and the hippocampus after five weeks of administration. In conclusion, our data demonstrates the possible protective effect of BCA against memory deterioration in mice fed with CPZ for five weeks