Inflammation-induced GDNF improves locomotor function after spinal cord injury

Abstract

Activation of microglia/macrophages after injury occurs limitedly in the CNS, which finding may explain unsuccessful axonal regeneration. Therefore, the relationship between lipopolysaccharide (LPS)-induced inflammation and recovery of locomotor function of rats after spinal cord injury was examined. High-dose LPS improved locomotor function greater than low-dose LPS, being consistent with the expression of neurotrophic factor (GDNF) in microglia/macrophages. Experiments using GDNF gene mutant mice confirmed that the increase in the GDNF mRNA level, rather than the reduction in the mRNA level of inducible NO synthase, could be correlated with the restoration activity of locomotor function. These results suggest that a higher degree of inflammation leads to a higher degree of repair of CNS injuries through GDNF produced by activated microglia/macrophages.

Driving GDNF expression: The green and the red traffic lights

“…However, both LPS and TNF-a trigger a significant decrease in the mRNA level of GFRa1 . In vivo, a high dose of LPS improves locomotor function after spinal cord injury in rats greater than a low dose, which is consistent with the expression of GDNF in microglia/macrophages (Hashimoto et al, 2005c). These results are in accordance with LPS-induced GDNF mRNA expression in microglial cultures (Tanaka et al, 2008).…”

“…The principal function of IL-10 appears to be limitation and ultimately termination of inflammatory responses (Moore et al, 2001). Therefore, the observation that AS101, which inhibits IL-10 and induces pro-inflammatory molecules, increases GDNF expression is consistent with the findings that pro-inflammatory molecules induce GDNF up-regulation (Appel et al, 1997;Verity et al, 1998Verity et al, , 1999McNaught and Jenner, 2000;Remy et al, 2003;Hashimoto et al, 2005c;Kuno et al, 2006). Also type-2A protein phosphatases (PP) seem to negatively regulate GDNF expression as GDNF levels increase upon their inhibition (Verity et al, 1998).…”

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

“…Microglia participate in the removal of myelin debris, produce growth factors including glial cell line derived neurotrophic factor (29) that are favorable for neurite growth and regeneration (30) , and express transforming growth factorbeta1 (TGF-beta1), a cytokine/growth factor that inhibits the release of cytotoxic molecules, decreases astrocyte proliferation, and promotes neuronal survival (31) .…”

Role of Microglia in Inflammatory Process in Parkinson’s Disease

“…Neurotrophic effects of microglial activation were reported in cell-culture studies (Elkabes et al, 1996(Elkabes et al, , 1998Miwa et al, 1997;Nagata et al, 1993a;Nakajima et al, 2001) and in studies using animal models of neurodegeneration (Hashimoto et al, 2005;Imai et al, 1999Imai et al, , 2007Rabchevsky and Streit, 1997;Suzuki et al, 2001). In neonatal (P8) mice (A-C), dopaminergic (A9) neurons in the SN were decreased in MPTP-treated mice, whereas these neurons in the LPS-MPTP-treated mice were recovered, compared from MPTP-treated mice.…”

“…Stimulation by LPS increases the microglial secretion of NT-3, NT-4/5, NGF, and BDNF (Elkabes et al, 1998;Miwa et al, 1997;Nakajima et al, 2001). A rat model of spinal cord injury showed improvement in locomotor function by an LPS-elicited increase in the level of neuroprotective GDNF (Hashimoto et al, 2005). Plasminogen produced by LPS-treated microglia was reported to promote the development of dopaminergic neurons (Nagata et al, 1993b;Nakajima et al, 1992).…”