Neuroprotection induced by vitamin E against oxidative stress in hippocampal neurons: Involvement of TRPV1 channels (original) (raw)
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The contribution of TRPV1 channel to 20-HETE—Aggravated ischemic neuronal injury
Prostaglandins & Other Lipid Mediators, 2018
20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 (CYP) 4A/4F-derived metabolite of arachidonic acid, directly contributes to ischemic neuronal injury. However, little is known about mediators of 20-HETE neurotoxicity after ischemia. Here, we focus on the role of transient receptor potential cation channel subfamily V member 1 (TRPV1) in 20-HETE-induced neurotoxicity. Our results showed that TRPV1 and CYP4A immunoreactivity were colocalized in neurons. TRPV1 inhibition attenuated 20-HETE mimetic 20-5,14-HEDGE-induced reactive oxygen species (ROS) production and neuronal injury in cultured neurons and protected ischemic neurons in vitro and in vivo. TRPV1 inhibition in combination with 20-HETE synthesis inhibitor HET0016 did not produce additional protective effects. Furthermore, TRPV1 genetic inhibition and NADPH oxidase inhibitor gp91ds-dat each attenuated ROS production to a similar extent. However, combined treatment did not achieve additional reduction. Therefore, we conclude that TRPV1 channels are involved in 20-HETE's ROS generation and neurotoxicity after ischemia.
Free Radical Biology and Medicine, 2005
Neuroprotection exerted by a-tocopherol against oxidative stress was investigated in cultured rat hippocampal neurons. In addition to its direct action as a radical scavenger revealed at concentrations above 10 AM, a transient application of 1 AM a-tocopherol phosphate (a-TP) to neurons induced a complete delayed long-lasting protection against oxidative insult elicited by exposure to Fe 2+ ions, but not against excitotoxicity. A minimal 16-h application of a-TP was required to observe the protection against subsequent oxidative stress. This delayed protection could last up to a week after the application of a-TP, even when medium was changed after the a-TP treatment. Cycloheximide, added either 2 h before or together with a-TP, prevented the delayed neuroprotection, but not the acute. However, cycloheximide applied after the 16-h a-TP pretreatment did not alter the delayed neuroprotection. Neither Trolox, a cell-permeant analogue of a-tocopherol, nor other antioxidants, such as epigallocatechin-gallate and N-acetyl-l-cysteine, elicited a similar long-lasting protection. Only tertbutylhydroquinone could mimic the a-TP effect. Depletion of glutathione (GSH) by l-buthionine sulfoximine did not affect the delayed a-TP protection. Thus, in addition to its acute anti-radical action, a-TP induces a long-lasting protection of neurons against oxidative damage, via a genomic action on antioxidant defenses apparently unrelated to GSH biosynthesis. D Oxidative stress due to an excessive accumulation of reactive oxygen species (ROS), including O 2 0891-5849/$ -see front matter D
Developmental Brain Research, 2001
In the immature brain hydrogen peroxide accumulates after excitotoxic hypoxia-ischemia and is neurotoxic. Immature hippocampal neurons were exposed to N-methyl-D-aspartate (NMDA), a glutamate agonist, and hydrogen peroxide (H O ) and the effects of free 2 2 radical scavenging and transition metal chelation on neurotoxicity were studied. a-Phenyl-N-tert.-butylnitrone (PBN), a known superoxide scavenger, attenuated both H O and NMDA mediated toxicity. Treatment with desferrioxamine (DFX), an iron chelator, at 2 2 the time of exposure to H O was ineffective, but pretreatment was protective. DFX also protected against NMDA toxicity. TPEN, a 2 2 metal chelator with higher affinities for a broad spectrum of transition metal ions, also protected against H O toxicity but was ineffective 2 2 against NMDA induced toxicity. These data suggest that during exposure to free radical and glutamate agonists, the presence of iron and other free metal ions contribute to neuronal cell death. In the immature nervous system this neuronal injury can be attenuated by free radical scavengers and metal chelators.
Molecular Brain, 2021
To understand the role of intracellular zinc ion (Zn2+) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-β (Aβ) peptides, this study aimed to investigate whether N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, could attenuate Aβ25–35-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn2+ in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K+) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aβ25–35-induced neuronal death, reversed the Aβ25–35-induced increase in in...
Scientific Reports, 2016
neuroprotective roles of DEX were tested on cerebral ischemia (ISC) in the cultures of rat primary hippocampal and DRG neurons. Fifty-six rats were divided into five groups. A placebo was given to control, sham control, and ISC groups, respectively. In the third group, ISC was induced. The DEX and ISC+DEX groups received intraperitoneal DEX (40 μg/kg) 3, 24, and 48 hours after ISC induction. DEX effectively reversed capsaicin and cumene hydroperoxide/ADP-ribose-induced TRPV1 and TRPM2 densities and cytosolic calcium ion accumulation in the neurons, respectively. In addition, DEX completely reduced ISC-induced oxidative toxicity and apoptosis through intracellular reactive oxygen species production and depolarization of mitochondrial membrane. The DEX and ISC+DEX treatments also decreased the expression levels of caspase 3, caspase 9, and poly (ADP-ribose) polymerase in the hippocampus and DRG. In conclusion, the current results are the first to demonstrate the molecular level effects of DEX on TRPM2 and TRPV1 activation. Therefore, DEX can have remarkable neuroprotective impairment effects in the hippocampus and DRG of ISC-induced rats.
PLoS ONE, 2012
The polymodal transient receptor potential vanilloid 4 (TRPV4) channel, a member of the TRP channel family, is a calciumpermeable cationic channel that is gated by various stimuli such as cell swelling, low pH and high temperature. Therefore, TRPV4-mediated calcium entry may be involved in neuronal and glia pathophysiology associated with various disorders of the central nervous system, such as ischemia. The TRPV4 channel has been recently found in adult rat cortical and hippocampal astrocytes; however, its role in astrocyte pathophysiology is still not defined. In the present study, we examined the impact of cerebral hypoxia/ischemia (H/I) on the functional expression of astrocytic TRPV4 channels in the adult rat hippocampal CA1 region employing immunohistochemical analyses, the patch-clamp technique and microfluorimetric intracellular calcium imaging on astrocytes in slices as well as on those isolated from sham-operated or ischemic hippocampi. Hypoxia/ischemia was induced by a bilateral 15-minute occlusion of the common carotids combined with hypoxic conditions. Our immunohistochemical analyses revealed that 7 days after H/I, the expression of TRPV4 is markedly enhanced in hippocampal astrocytes of the CA1 region and that the increasing TRPV4 expression coincides with the development of astrogliosis. Additionally, adult hippocampal astrocytes in slices or cultured hippocampal astrocytes respond to the TRPV4 activator 4-alpha-phorbol-12,-13-didecanoate (4aPDD) by an increase in intracellular calcium and the activation of a cationic current, both of which are abolished by the removal of extracellular calcium or exposure to TRP antagonists, such as Ruthenium Red or RN1734. Following hypoxic/ischemic injury, the responses of astrocytes to 4aPDD are significantly augmented. Collectively, we show that TRPV4 channels are involved in ischemiainduced calcium entry in reactive astrocytes and thus, might participate in the pathogenic mechanisms of astroglial reactivity following ischemic insult. Citation: Butenko O, Dzamba D, Benesova J, Honsa P, Benfenati V, et al. (2012) The Increased Activity of TRPV4 Channel in the Astrocytes of the Adult Rat Hippocampus after Cerebral Hypoxia/Ischemia. PLoS ONE 7(6): e39959.
Comparative Effects of Heterologous TRPV1 and TRPM8 Expression in Rat Hippocampal Neurons
PLOS One, 2009
Heterologous channel expression can be used to control activity in select neuronal populations, thus expanding the tools available to modern neuroscience. However, the secondary effects of exogenous channel expression are often left unexplored. We expressed two transient receptor potential (TRP) channel family members, TRPV1 and TRPM8, in cultured hippocampal neurons. We compared functional expression levels and secondary effects of channel expression and activation on neuronal survival and signaling. We found that activation of both channels with appropriate agonist caused large depolarizing currents in voltage-clamped hippocampal neurons, exceeding the amplitude responses to a calibrating 30 mM KCl stimulation. Both TRPV1 and TRPM8 currents were reduced but not eliminated by 4 hr incubation in saturating agonist concentration. In the case of TRPV1, but not TRPM8, prolonged agonist exposure caused strong calcium-dependent toxicity. In addition, TRPV1 expression depressed synaptic transmission dramatically without overt signs of toxicity, possibly due to low-level TRPV1 activation in the absence of exogenous agonist application. Despite evidence of expression at presynaptic sites, in addition to somatodendritic sites, TRPM8 expression alone exhibited no effects on synaptic transmission. Therefore, by a number of criteria, TRPM8 proved the superior choice for control over neuronal membrane potential. This study also highlights the need to explore potential secondary effects of long-term expression and activation of heterologously introduced channels.
Journal of Biological …, 2005
Mammalian homologues of the Drosophila canonical transient receptor potential (TRP) proteins have been implicated to function as plasma membrane Ca 2؉ channels. This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells. SH-SY5Y cells treated with an exogenous neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP ؉) significantly decreased TRPC1 protein levels. Confocal microscopy on SH-SY5Y cells treatment with MPP ؉ showed decreased plasma membrane staining of TRPC1. Importantly, overexpression of TRPC1 reduced neurotoxicity induced by MPP ؉. MPP ؉-induced ␣-synuclein expression was also suppressed by TRPC1 overexpression. Protection of SH-SY5Y cells against MPP ؉ was significantly decreased upon the overexpression of antisense TRPC1 cDNA construct or the addition of a nonspecific transient receptor potential channel blocker lanthanum. Activation of TRPC1 by thapsigargin or carbachol decreased MPP ؉ neurotoxicity, which was partially dependent on external Ca 2؉. Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protects SH-SY5Y neuronal cells against apoptosis. Further, TRPC1 overexpression inhibited cytochrome c release and decreased Bax and Apaf-1 protein levels. Interpretation of the above data suggests that reduction in the cell surface expression of TRPC1 following MPP ؉ treatment may be involved in dopaminergic neurodegeneration. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents.
TRP Channels: New Potential Therapeutic Approaches in CNS Neuropathies
CNS & Neurological Disorders - Drug Targets, 2013
More than 30 different Transient Receptor Potential channels (TRP) have been identified in mammals and are grouped in 6 families. Members of these subunit families, specifically of the vanilloid TRP (TRPV), melastatin TRP (TRPM), ankyrin TRP (TRPA), polycystin TRP (TRPP) and canonical or classical TRP (TRPC) family, are considered relevant in central nervous system neurodegenerative diseases. In fact, TRP channels have received increased attention in recent years, since they are involved in a broad array of pathways and respond to different environmental stimuli. Preclinical research has identified TRPs involved in hereditary neuropathies as well as in a heterogeneous group of neuronal disorders. Moreover, changes in TRP channel expression and functionality have been associated to diabetic thermal hyperalgesia, painful neuropathies and headache. At the molecular level, TRPs are involved in a wide range of mechanisms regulating osmosis, thermal, stretch, chemical and sensory signaling, highlighting TRPs as potential targets for pharmacological intervention. The area of small molecule TRP agonists/antagonists drug development is moving rapidly. This review will evaluate current evidence that supports particular TRP channels as targets for novel drugs, summarizing the current perspectives for the therapeutic potential of TRP agonists and antagonists in the treatment of a wide range of neuropathies, along with potential adverse effects that may limit drug development.
Anti-Cancer Drugs, 2020
As a member of the platinum drug group, oxaliplatin (OXAL) is used to treat brain tumors, although its use is limited through excessive calcium ion (Ca 2+) influx and reactive oxygen species (ROS) production in neurons. The Ca 2+ permeable transient receptor potential vanilloid 1 (TRPV1) channel is activated by ROS, and its activity might be reduced by the antioxidant property of pregabalin (PREGAB). This study aimed to investigate the protective action of PREGAB against OXAL-induced oxidative neurotoxicity in human glioblastoma (DBTRG) cells. The DBTRG cells were divided into four treatment groups: control, PREGAB (500 µM for 1 h), OXAL (25 µM for 24 h), and PREGAB + OXAL. In the laser confocal microscope and plate reader analyses, apoptosis, mitochondrial membrane depolarization (JC-1), cell death (propidium iodide/Hoechst rate), and ROS-level production increased by activating TRPV1 in the cells using the OXAL treatment, although the cell viability values decreased. However, these values were recovered in the PREGAB + OXAL group using PREGAB and TRPV1 inhibitor (capsazepine) treatments. In the patch-clamp analyses, OXAL-induced TRPV1 channel activation in the OXAL group also decreased in the PREGAB + OXAL group using the PREGAB and capsazepine treatments. In conclusion, the apoptosis and oxidant actions of OXAL were increased by activation of the TRPV1 channel, but this effect was diminished by the PREGAB treatment. PREGAB treatment has the potential to be an effective strategy in the treatment of OXAL-induced oxidative neurotoxicity.