Pyrethroid Insecticides Directly Activate Microglia Through Interaction With Voltage-Gated Sodium Ch

[pattismith]

Toxicol Sci. 2017
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Pyrethroid Insecticides Directly Activate Microglia Through Interaction With Voltage-Gated Sodium Channels.

Abstract

Microglia are considered to be the resident immune cells of the central nervous system and contribute significantly to ongoing neuroinflammation in a variety of neurodegenerative diseases.

Recently, we and others identified that voltage-gated sodium channels (VGSC) are present on microglia cells and contribute to excessive accumulation of intracellular Na+ and release of major pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α).

Based on this finding and the fact that pyrethroid pesticides act on VGSC, we hypothesized that exposure of microglia to the pyrethroid pesticides, permethrin and deltamethrin, would activate microglia and increase the release of TNF-α.

BV2 cells or primary microglia were treated with 0-5 µM deltamethrin or permethrin in the presence or absence of tetrodotoxin (TTX), a VGSC blocker for 24-48 h.

Both pyrethroids caused a rapid Na+ influx and increased accumulation of intracellular sodium [(Na+)i] in the microglia in a dose- and time-dependent manner, which was significantly reduced by TTX.

Furthermore, deltamethrin and permethrin increased the release of TNF-α in a dose- and time-dependent manner, which was significantly reduced by pre-treatment of cells with TTX.

These results demonstrate that pyrethroid pesticides may directly activate microglial cells through their interaction with microglial VGSC.
Because neuroinflammation plays a key role in many neurodegenerative diseases, these data provide an additional mechanism by which exposure to pyrethroid insecticides may contribute to neurodegeneration.

 

[pattismith]

Toxicol Appl Pharmacol. 2013
Coordinated role of voltage-gated sodium channels and the Na+/H+ exchanger in sustaining microglial activation during inflammation.

Abstract
Persistent neuroinflammation and microglial activation play an integral role in the pathogenesis of many neurological disorders. We investigated the role of voltage-gated sodium channels (VGSC) and Na(+)/H(+) exchangers (NHE) in the activation of immortalized microglial cells (BV-2) after lipopolysaccharide (LPS) exposure.

LPS (10 and 100 ng/ml) caused a dose- and time-dependent accumulation of intracellular sodium [(Na(+))i] in BV-2 cells. Pre-treatment of cells with the VGSC antagonist tetrodotoxin (TTX, 1 μM) abolished short-term Na(+) influx, but was unable to prevent the accumulation of (Na(+))i observed at 6 and 24h after LPS exposure. The NHE inhibitor cariporide (1 μM) significantly reduced accumulation of (Na(+))i 6 and 24h after LPS exposure. Furthermore, LPS increased the mRNA expression and protein level of NHE-1 in a dose- and time-dependent manner, which was significantly reduced after co-treatment with TTX and/or cariporide.

LPS increased production of TNF-α, ROS, and H2O2 and expression of gp91(phox), an active subunit of NADPH oxidase, in a dose- and time-dependent manner, which was significantly reduced by TTX or TTX+cariporide. Collectively, these data demonstrate a closely-linked temporal relationship between VGSC and NHE-1 in regulating function in activated microglia, which may provide avenues for therapeutic interventions aimed at reducing neuroinflammation.

 

[pattismith]

Glia. 2013
An increase in voltage-gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury.

Abstract
Inflammation induced by microglial activation plays a pivotal role in progressive degeneration after traumatic spinal cord injury (SCI).
Voltage-gated sodium channels (VGSCs) are also implicated in microglial activation following injury. However, direct evidence that VGSCs are involved in microglial activation after injury has not been demonstrated yet.
Here, we show that the increase in VGSC inward current elicited microglial activation followed inflammatory responses, leading to cell death after injury in vitro and in vivo.

Isoforms of sodium channel, Nav 1.1, Nav 1.2, and Nav 1.6 were expressed in primary microglia, and the inward current of VGSC was increased by LPS treatment, which was blocked by a sodium channel blocker, tetrodotoxin (TTX).
TTX inhibited LPS-induced NF-κB activation, expression of TNF-α, IL-1β and inducible nitric oxide synthase, and NO production.
LPS-induced p38MAPK activation followed pro-nerve growth factor (proNGF) production was inhibited by TTX, whereas LPS-induced JNK activation was not. TTX also inhibited caspase-3 activation and cell death of primary cortical neurons in neuron/microglia co-cultures by inhibiting LPS-induced microglia activation.
Furthermore, TTX attenuated caspase-3 activation and oligodendrocyte cell death at 5 d after SCI by inhibiting microglia activation and p38MAPK activation followed proNGF production, which is known to mediate oligodendrocyte cell death.
Our study thus suggests that the increase in inward current of VGSC appears to be an early event required for microglia activation after injury.