In vitro models to study mechanisms of neural cell death induced by toxic agents
Author: Tofighi, Roshan
Date: 2007-12-20
Location: Samuelssonsalen, Tomtebodavägen 6, Karolinska Institutet
Time: 09.00
Department: Institutet för miljömedicin (IMM) / Institute of Enviromental Medicine
Abstract
Neurotoxicity arises when exposure to toxic agents, either naturally
occurring or manmade substances, alters the normal activity and/or
structure of the nervous system. This can lead to disruption of vital
metabolic processes and eventually to cell death. Certain unique features
of the nervous system make it particularly vunerable to toxicants, e.g.
its high demand of energy, high content of polyunsaturated fatty acids
and low levels of antioxidant enzymes. In this thesis, we have
investigated the mechanisms leading to neurotoxic cell death and the role
of ion channels in neural apoptosis by using different in vitro
experimental models. Such models offer unique advantages in elucidating
mechanisms of toxicity, and hence are used to understand the consequences
of exposure to toxicants.
Occupational exposure to styrene in industrial workers has been
associated with neurobehavioral deficits. Alterations of
neurotransmitters and loss of neurons have also been observed in in vivo
models. The main metabolite of styrene, styrene 7,8-oxide (SO), is
believed to account for most of styrene s toxicity. Carbon monoxide (CO),
an endogenous gas, plays important physiological roles, but CO poisoning
due to accidental or intentional exposure, occurs frequently. CO has
higher affinity for hemoglobin than oxygen, and brain hypoxia due to the
binding of CO to hemoglobin is a recognized cause of CO neurotoxicity.
However, the direct effect of CO on intracellular targets is still not
well understood. We have characterized the cellular damage induced by SO
and CO in different in vitro models. Our data show that SO causes
apoptosis via activation of caspases and that its neurotoxic effects are
related to mitochondrial damage and oxidative stress. CO induces
hypoxia-independent apoptotic cell death via parallel activation of both
caspases and calpains.
Cell shrinkage is an early morphological feature occurring during
apoptosis that is associated with an increased efflux of K+ and Cl- ions.
We investigated the role of ion channels in differentiated and
non-differentiated neural cells undergoing apoptosis. Our results point
to a novel function of the voltage-dependent anion channel in the plasma
membrane (pl-VDAC) playing a role in the early phase of neuronal
apoptosis. In contrast, pl-VDAC is scarcely seen in apoptotic cortical
neural stem cells and instead, an amiloride-sensitive Na+-channel is
activated. Thus, it appears that neurons and neural stem cells utilize
different apoptotic strategies.
With appropriate in vitro models we have been able to characterize the
intracellular pathways affected by SO and CO, and to demonstrate
activation of different ion channels during apoptosis in undifferentiated
and differentiated neural cells. There is an increasing consensus on in
vitro models being useful tools to test neurotoxic agents and dissect
their mechanisms of action. In fact, by using multiple cell models it is
possible to recognize specific patterns of toxicity of different
neurotoxicants and use this information for risk assessement.
List of papers:
I. Daré E, Tofighi R, Vettori MV, Momoi T, Poli D, Saido TC, Mutti A, Ceccatelli S. (2002). "Styrene 7,8-oxide induces caspase activation and regular DNA fragmentation in neuronal cells." Brain Res 933(1): 12-22
Pubmed
II. Daré E, Tofighi R, Nutt L, Vettori MV, Emgård M, Mutti A, Ceccatelli S. (2004). "Styrene 7,8-oxide induces mitochondrial damage and oxidative stress in neurons." Toxicology 201(1-3): 125-32
Pubmed
III. Tofighi R, Tillmark N, Daré E, Aberg AM, Larsson JE, Ceccatelli S. (2006). "Hypoxia-independent apoptosis in neural cells exposed to carbon monoxide in vitro." Brain Res 1098(1): 1-8
Pubmed
IV. Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S. (2005). "Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli." Cell Death Differ 12(8): 1134-40
Pubmed
V. Akanda N, Tofighi R, Brask J, Tamm C, Elinder F, Ceccatelli S. (1970). "Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells." Journal of Neuroscience (Submitted)
I. Daré E, Tofighi R, Vettori MV, Momoi T, Poli D, Saido TC, Mutti A, Ceccatelli S. (2002). "Styrene 7,8-oxide induces caspase activation and regular DNA fragmentation in neuronal cells." Brain Res 933(1): 12-22
Pubmed
II. Daré E, Tofighi R, Nutt L, Vettori MV, Emgård M, Mutti A, Ceccatelli S. (2004). "Styrene 7,8-oxide induces mitochondrial damage and oxidative stress in neurons." Toxicology 201(1-3): 125-32
Pubmed
III. Tofighi R, Tillmark N, Daré E, Aberg AM, Larsson JE, Ceccatelli S. (2006). "Hypoxia-independent apoptosis in neural cells exposed to carbon monoxide in vitro." Brain Res 1098(1): 1-8
Pubmed
IV. Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S. (2005). "Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli." Cell Death Differ 12(8): 1134-40
Pubmed
V. Akanda N, Tofighi R, Brask J, Tamm C, Elinder F, Ceccatelli S. (1970). "Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells." Journal of Neuroscience (Submitted)
Issue date: 2007-11-29
Publication year: 2007
ISBN: 978-91-7357-459-4
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