Insulin-like growth factor-II increases and IGF is required for postnatal rat spinal motoneuron survival following sciatic nerve axotomy

Abstract

The prolonged disconnection of nerve from muscle results in the death of motoneurons and permanent paralysis. Because clinical nerve injuries generally involve postbirth motoneurons, there is interest in uncovering factors that may support their survival. A rich history of research dating back to the time of Santiago Ramon y Cajal and Viktor Hamburger supports the inference that there are soluble neurotrophic factors associated with nerve and muscle. However, the endogenous factors normally required for motoneuron survival following nerve injury have eluded identification. Two interrelated hypotheses were tested: (1) administration of insulin-like growth factor-II (IGF-II) can support the survival of postbirth motoneurons, and (2) endogenous IGFs are essential for motoneuron survival following nerve injury. We report that IGF-II locally administered close to the proximal nerve stump prevented the death of motoneurons (estimated by relative numbers of neuronal profiles) which ordinarily follows sciatic nerve transection in neonatal rats. By contrast, anti-IGF antiserum, as well as IGF binding proteins-4 and -6, significantly increased (P < 0.01) motoneuron death. This report shows that IGF-II can support survival, and contains the novel observation that endogenous IGF activity in or near nerves is required for motoneuron survival. Other studies have determined that IGF gene and protein expression are increased in nerve and muscle following sciatic nerve crush, and that IGFs are required for nerve regeneration. Taken together, these data show that IGFs are nerve- and muscle-derived soluble factors that support motoneuron survival as well as nerve regeneration.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation

“…Injury during early life however, has been shown to alter DH neuron development, which can induce altered behavioral responsiveness to thermal and mechanical stimuli in adulthood [36,51,68,69]. It has been hypothesized that this phenomenon is due to altered peripheral A-fiber sensitization along with improper development of glycinergic inhibition [25,27]; a notion that was recently supported by our laboratory [24].…”

“…For example, there is a known switch in neurotrophic factor sensitivity during the first week of life, whereby sensory neurons downregulate trkA and upregulate c-ret rendering them responsive to glial cell line-derived neurotrophic factor (GDNF) instead of nerve growth factor (NGF) [41,47]. This switch subsequently regulates how the sensory neurons relay information from the periphery to the spinal dorsal horn (DH) [28,51,54]. …”

Calcium-dependent protein folding in amyotrophic lateral sclerosis

“…During ER stress, IGF-I potentiates the UPR by enhancing the folding capacity via inducing Grp78 expression [139]. Moreover, the soluble muscleand nerve-derived neurotropic factors IGF-I and IGF-II stimulate proteins-synthesis, promote survival and differentiation of motor neurons, and mediate anti-apoptotic signalling by inducting mitogen activated protein kinases (MAPK) as well as PI3K/AKT/mTOR signalling [140,141]. IGF-I levels were higher and IGF-II levels were significantly lower in patients with ALS than in healthy controls [142,143], suggesting that motor neuron degeneration could lead to a compensatory increase in IGF-I to provide additional support for motor neurons.…”

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation: Erratum.

“…Injury during early life however, has been shown to alter DH neuron development, which can induce altered behavioral responsiveness to thermal and mechanical stimuli in adulthood [36,51,68,69]. It has been hypothesized that this phenomenon is due to altered peripheral Afiber sensitization along with improper development of glycinergic inhibition [25,27]; a notion that was recently supported by our laboratory [24].…”