Effects of systemic administration of ciliary neurotrophic factor on Bax and Bcl-2 proteins in the lumbar spinal cord of neonatal rats after sciatic nerve transection

Abstract

Ciliary neurotrophic factor (CNTF) is a cytokine that plays a neuroprotective role in relation to axotomized motoneurons. We determined the effect of daily subcutaneous doses of CNTF (1.2 µg/g for 5 days; N = 13) or PBS (N = 13) on the levels of mRNA for Bcl-2 and Bax, as well as the expression and inter-association of Bcl-2 and Bax proteins, and the survival of motoneurons in the spinal cord lumbar enlargement of 2-day-old Wistar rats after sciatic nerve transection. Five days after transection, the effects were evaluated on histological and molecular levels using Nissl staining, immunoprecipitation, Western blot analysis, and reverse transcriptase-polymerase chain reaction. The motoneuron survival ratio, defined as the ratio between the number of motoneurons counted on the lesioned side vs those on the unlesioned side, was calculated. This ratio was 0.77 ± 0.02 for CNTF-treated rats vs 0.53 ± 0.02 for the PBS-treated controls (P < 0.001). Treatment with CNTF modified the level of mRNA, with the expression of Bax RNA decreasing 18% (with a consequent decrease in the level of Bax protein), while the expression of Bcl-2 RNA was increased 87%, although the level of Bcl-2 protein was unchanged. The amount of Bcl-2/Bax heterodimer increased 91% over that found in the PBS-treated controls. These data show, for the first time, that the neuroprotective effect of CNTF on neonatal rat axotomized motoneurons is associated with a reduction in free Bax, due to the inhibition of Bax expression, as well as increased Bcl-2/Bax heterodimerization. Thus, the neuroprotective action of the CNTF on axotomized motoneurons can be related to the inhibition of this apoptotic pathway.

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

“…In addition, CNTF protected mouse liver and HEPG2 cells against alloxan-induced apoptosis, as indicated by lower cleaved caspase 3/pro-caspase 3 ratio, and this effect probably occurs through STAT3 upregulation and STAT1 downregulation (ESM Fig. 4), similarly to that observed in neuronal cells [43,44] and pancreatic islets [13]. The protective effects of CNTF on mouse liver could also help to, at least in part, explain how CNTF is able to reduce hepatic steatosis and inflammation, but this is a subject yet to be explored.…”

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

“…Phosphorylation inactivates Bcl-2, thus promoting apoptosis, possibly by releasing Bax from Bcl-2/Bax dimers [62][63][64]. The Bcl-2/Bax heterodimer is the active component for death protection [65,66]. In response to apoptotic stimulation, Bax can be released from Bcl-2/Bax dimers and act as the channels for either ions or proteins [64,67].…”

Ciliary Neurotrophic Factor Protects Mice Against Streptozotocin-induced Type 1 Diabetes through SOCS3

“…CNTF is distributed throughout the rat central and peripheral nervous system, in neurons, glial, and Schwann cells (6,7), and acts as a survival factor for neurons (8) and pancreatic islets (9). Although CNTF impairs glucose-stimulated insulin secretion (9,10), it is antidiabetogenic and exhibits many in vivo systemic effects, such as a reduction in adiposity, body weight, hyperinsulinemia, and hyperglycemia in rats (11)(12)(13)(14)(15)(16)(17)(18).…”