Endogenous Repair by the Activation of Cell Survival Signalling Cascades during the Early Stages of Rat Parkinsonism

Abstract

Here we report a previously unknown self repair mechanism during extremely early stages of rat Parkinsonism. Two important cell survival signaling cascades, Phosphatidylinositol-3 kinases (PI3K)/Akt pathway and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, could be responsible for this potential endogenous rescue system. In the 6-hydroxydopamine-lesioned rat, the phosphorylated p44/42 MAPK and its downstream target, the phosphorylated Bad at Ser 112, were up-regulated at post-lesion day 3 and lasted for a couple of weeks. Although the change in the phosphorylated Akt kinase was negligible throughout the studied period, its downstream target, the phosphorylated Bad at 136, was increased from post-lesion day 3 to post-lesion day 14. In the mean time, nestin-positive reactive astrocytes with low levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) appeared at post-lesion day 3 in 6-hydroxydopamine-lesioned rat. BDNF was expressed in both striatum and substantia nigra whereas GDNF was displayed in striatum only. At post-lesion day 14, nestin, BDNF and GDNF expressions were diminished. These neurotrophic factors were believed to initiate the above anti-apoptotic signal transduction cascades as we could see that their expression patterns were similar. The data strongly suggest that there is an endogenous repair effort by evoking the cell survival signaling and possibly via the releases of BDNF and GDNF from nestin-immunoreactive reactive astrocytes. ERK/MAPK pathway was proposed to be the key endogenous neuroprotective mechanisms, particularly in early stages of rat Parkinsonism. However, the self repair effort is only functional within an extremely short time window immediately after onset.

Caspase‐3 inhibition prevents the development of hepatopulmonary syndrome in common bile duct ligation rats by alleviating pulmonary injury

“…Acute pulmonary injury also affects newborns with intrahepatic cholestasis of pregnancy as well as patients with acute liver failure and cirrhosis . Once injured, self‐repair mechanisms are evoked, prompting the release of various growth factors and cytokines, such as vascular endothelial growth factor‐A and the chemokine fractalkine . These molecules activate survival signals, such as Akt and ERK, in turn leading to endothelial cells (ECs) proliferation and pathological angiogenesis .…”

“…Once injured, self‐repair mechanisms are evoked, prompting the release of various growth factors and cytokines, such as vascular endothelial growth factor‐A and the chemokine fractalkine . These molecules activate survival signals, such as Akt and ERK, in turn leading to endothelial cells (ECs) proliferation and pathological angiogenesis . These findings raise the possibility that this initial pulmonary injury plays a role in late angiogenesis following CBDL.…”

Simvastatin combined with bone marrow stromal cells treatment activatesastrocytes to ameliorate neurological function after ischemic stroke in rats

“…Under pathological conditions, astrocytes could release neurovascular trophic factors, e.g., glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), stromal cellderived factor-1 (SDF-1), and vascular endothelial growth factor (VEGF)-A (Miyazaki et al, 2001;Argaw et al, 2012;Mele and Jurič, 2014;Shin et al, 2014). As has been well demonstrated, SDF-1, BDNF, and GDNF were capable of activating the phosphatidylinositol 3-kinase (PI3K)/AKT and/or extracellular signal-regulated kinase/mitogenactivated protein kinase (ERK/MAPK) signaling pathways in glia, while the reactive PI3K/AKT signal pathway could further improve astrocytes to express VEGF and angiopoietin-1 (Ang1) Lui et al, 2012;Jang et al, 2014). Due to their pivotal role in the nervous system, astrocytes are now recognized as key participants in brain development, function, and disease.…”

Upregulation of p-Akt by glial cell line-derived neurotrophic factor ameliorates cell apoptosis in the hippocampus of rats with streptozotocin-induced diabetic encephalopathy

“…GDNF-epithelial growth factor receptor 1 (EGR1) pathway activation is critical in renal epithelial cell apoptosis and migration in diabetic renal embryopathy (13). In addition, GDNF, nestin and glial fibrillary acidic protein (GFAP)-positive reactive astrocytes appeared at an early stage in 6-hydroxydopamine-induced Parkinsonism in rats, which suggested the existence of endogenous neuroprotective mechanisms that act via the release of BDNF and GDNF from GFAP-positive immunoreactive astrocytes (14). However, one recent study indicated that GDNF treatment did not affect neuronal survival but another neurotrophic factor, neurotrophin 3, was able to enhance the survival of enteric ganglion cells in H 2 O 2 -treated cultures (15).…”

“…High intracellular activation of GDNF downstream pathways triggers neuronal differentiation, while low-level activation of GDNF signaling is crucial for the maintenance of the progenitor state (18). In addition, the ERK/MAPK pathway, instead of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway, was proposed to be the key endogenous neuroprotective mechanism, acting via the release of bone-derived neurotrophic factor (BDNF) and GDNF from nestin and GFAP-positive reactive astrocytes in the 6-hydroxydopamine-induced rat model of Parkinson's (14). Furthermore, a recent study demonstrated that mechanical and thermal hypersensitivity was correlated with the structural changes and loss of GDNF/ Akt signaling in injured limbs 7 days after chronic constrictive injury was induced.…”