Neuroprotection by diarylpropionitrile in mice with spinal cord injury

The initial impact of spinal cord injury (SCI) often results in inflammation leading to irreversible damage with consequent loss of locomotor function. Minimal recovery is achieved once permanent damage has occurred. Using a mouse model of SCI we observed a transitory increase followed by a rapid decline in gene expression and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular anti-oxidative genes. Immediate treatment with diarylpropionitrile (DPN), a non-steroidal selective estrogen receptor β ligand, resulted in a significant increase in Nrf2 levels, and reduction of inflammation and apoptosis compared to untreated SCI animals. Furthermore, DPN-treatment improved locomotor function within 7 days after induction of SCI. DPN acted through activation of PI3K/Akt pathway, known to be involved in down-regulation of apoptosis and up-regulation of cell survival in injured tissues. These findings suggest that immediate activation of cellular anti-oxidative stress mechanisms should provide protection against irreversible tissue damage and its profound detrimental effect on locomotor function associated with SCI

Connectivity and circuitry in a dish versus in a brain

In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients’ brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity. In this review, we survey recent attempts to study these issues in human induced pluripotent stem cell-derived neurons. Although progress has been made, there are still many hurdles to overcome before human induced pluripotent stem cell-derived neurons can fully recapitulate all of the above physiological properties of adult mature neurons. Moreover, proper integration of neurons into pre-existing circuitry still needs to be achieved. Nevertheless, in vitro neuronal stem cell-derived models hold great promise for clinical application in neurological diseases in the future

β-Amyloid 25-35 Peptide Reduces the Expression of Glutamine Transporter SAT1 in Cultured Cortical Neurons

β-Amyloid (Aβ) peptides may cause malfunction and death of neurons in Alzheimer’s disease. We investigated the effect of Aβ on key transporters of amino acid neurotransmission in cells cultured from rat cerebral cortex. The cultures were treated with Aβ(25-35) at 3 and 10 μM for 12 and 24 h followed by quantitative analysis of immunofluorescence intensity. In mixed neuronal–glial cell cultures (from P1 rats), Aβ reduced the concentration of system A glutamine transporter 1 (SAT1), by up to 50% expressed relative to the neuronal marker microtubule-associated protein 2 (MAP2) in the same cell. No significant effects were detected on vesicular glutamate transporters VGLUT1 or VGLUT2 in neurons, or on glial system N glutamine transporter 1 (SN1). In neuronal cell cultures (from E18 rats), Aβ(25-35) did not reduce SAT1 immunoreactivity, suggesting that the observed effect depends on the presence of astroglia. The results indicate that Aβ may impair neuronal function and transmitter synthesis, and perhaps reduce excitotoxicity, through a reduction in neuronal glutamine uptake

A genetically immortalized human stem cell line:A promising new tool for Alzheimer’s disease therapy

Amyloid-β peptides and hyper-phosphorylated tau are the main pathological hallmarks of Alzheimer’s disease (AD). Given the recent failure of several large-scale clinical trials and the lack of disease-modifying pharmacological treatments, there is an urgent need to develop alternative therapies. A clinical grade human CTX0E03 neural stem cell line has recently passed phase I trials in people with stroke. However, this cell line has not been investigated in other neurodegenerative disorders. This study investigates the survival of CTX0E03 cells under conditions based on the underlying AD pathology. Cell viability assays showed a concentration dependence of this cell line to the toxic effects of Aβ1-42, but not Aβ1-40, and okadaic acid, a phosphatase 2A inhibitor. Notably, CTX0E03 cell line displayed toxicity at concentrations significantly higher than both rat neural stem cells and those previously reported for primary cultures. These results suggest CTX0E03 cells could be developed for clinical trials in AD patients

Aβ₁₋₄₂ stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor

The generation of amyloid-beta peptide (A beta) and its accumulation in amyloid plaques are generally recognized as key characteristics of Alzheimer's disease. A number of reports have indicated that A beta can regulate the proliferation of neural precursor cells and adult neurogenesis, suggesting that this may underpin the cognitive decline and compromised olfaction also associated with the condition. Here we report that A beta(1-42) treatment both in vitro and in vivo, as well as endogenous generation of A beta in C 100 and APP/PS1 transgenic models of Alzheimer's disease. stumulate neurogenesis of young adult subventricular zone precursors The neurogenic effect of A beta(1-42) was found to require expression of the p75 neurotrophin receptor (p75(NTR)) by the. precursor cells, and activation of p75(NTR) by metalloprotease cleavage However, precursors from 12-month-old APP/PS1 mice failed to respond to A beta(1-42), Our results suggest that overstunulation of p75(NTR)-positive progenitors during early life might result in depletion of the stein cell pool and thus a more rapid decline in basal neurogenesis. This, in turn, could lead to impaired neurogenic function in later life. (C) 2008 Elsevier Inc All rights reserve

Protective Roles of N-trans-feruloyltyramine Against Scopolamine-Induced Cholinergic Dysfunction on Cortex and Hippocampus of Rat Brains

Objective: To study the protective effects of N-trans-feruloyltyramine (NTF) on scopolamine-induced cholinergic dysfunction, apoptosis, and inflammation in rat brains. Materials and Methods: Treatments were administered intraperitoneally (i.p.). Wistar rats (8-week-old) were allocated into 4 groups (n = 3) as follows: scopolamine-only, NTF-only, NTF + scopolamine and control. Spatial cognition was evaluated by Morris water maze. ROS assay and Western blot analyses were conducted in 3 brain regions: the frontal cortex, hippocampus, and temporal cortex. Results: NTF treatment inhibited scopolamine-induced memory impairment and significantly attenuated scopolamine-induced changes in the three brain regions. Investigated scopolamine-associated changes were as follows: increases in ROS production and BACE1 level, decrease in ChAT level, increases in inflammatory and apoptotic markers, and activation of signaling pathway kinases related to inflammation and apoptosis. Conclusion: With its in vivo antioxidant, cholinergic-promoting, anti-apoptosis, and anti-inflammatory biological activities, NTF is a promising candidate to be further investigated as a potential treatment for Alzheimer’s-associated neurodegeneration

Connectivity and circuitry in a dish versus in a brain

In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients’ brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity. In this review, we survey recent attempts to study these issues in human induced pluripotent stem cell-derived neurons. Although progress has been made, there are still many hurdles to overcome before human induced pluripotent stem cell-derived neurons can fully recapitulate all of the above physiological properties of adult mature neurons. Moreover, proper integration of neurons into pre-existing circuitry still needs to be achieved. Nevertheless, in vitro neuronal stem cell-derived models hold great promise for clinical application in neurological diseases in the future

Neuroprotection of N-benzylcinnamide on scopolamine-induced cholinergic dysfunction in human SH-SY5Y neuroblastoma cells

Alzheimer's disease, a progressive neurodegenerative disease, affects learning and memory resulting from cholinergic dysfunction. Scopolamine has been employed to induce Alzheimer's disease-like pathology in vivo and in vitro through alteration of cholinergic system. N-benzylcinnamide (PT-3), purified from Piper submultinerve, has been shown to exhibit neuroprotective properties against amyloid-β-induced neuronal toxicity in rat cortical primary cell culture and to improve spatial learning and memory of aged rats through alleviating oxidative stress. We proposed a hypothesis that PT3 has a neuroprotective effect against scopolamine-induced cholinergic dysfunction. PT-3 (125–200 nM) pretreatment was performed in human neuroblastoma SH-SY5Y cell line following scopolamine induction. PT-3 (125–200 nM) inhibited scopolamine (2 mM)-induced generation of reactive oxygen species, cellular apoptosis, upregulation of acetylcholinesterase activity, downregulation of choline acetyltransferase level, and activation of p38 and JNK signalling pathways. These findings revealed the underlying mechanisms of scopolamine-induced Alzheimer's disease-like cellular dysfunctions, which provide evidence for developing drugs for the treatment of this debilitating disease

Curcumin Attenuates Hydrogen Peroxide-Induced Cytotoxicity in Human Neuroblastoma SK-N-SH Cells

Objective: Cellular damage induced by oxidative stress has been involved in the development of neurodegeneration. Curcumin, a dietary polyphenol found in the rhizome of Curcuma longa, has been shown, both in vitro and in vivo, to be an effective reactive oxygen scavenging molecule. We investigated an anti-oxidative effect of curcumin against H2 O2 -induced toxicity in human neuroblastoma cell line SK-N-SH. Methods: The SK-N-SH cells were pre-treated with curcumin 2 hours prior to H2 O2 treatment. We measured cell viability, intracellular reactive oxygen species (ROS) levels, expression of apoptotic-related proteins and caspase-3 activity 24 hours post H2 O2 -induced cytoxicity. Results: Treatment with curcumin at concentrations ranging from 5 to 50 μg/mL was not cytotoxic. Pre-treatment with curcumin at the concentrations of 5 to 50 μg/mL prior to H2 O2 exposure caused a significant decrease in intracellular ROS levels and a significant increase in cell viability in a dose-dependent manner. Expression of activated form of caspase-3 and BAX, a pro-apoptotic protein, measured by Western blotting were reduced when the SK-N- SH cell line was pre-incubated with curcumin. The curcumin pre-treated cells also exhibited less caspase-3 activity. Conclusion: Curcumin has protective effects against H2 O2 -induced toxicity in a dose-dependent manner through its anti-apoptotic and anti-oxidative properties in an in vitro H2 O2 -treated SK-N-SH model