Circulating Insulin-Like Growth Factor I Mediates the Protective Effects of Physical Exercise against Brain Insults of Different Etiology and Anatomy

Abstract

Physical exercise ameliorates age-related neuronal loss and is currently recommended as a therapeutical aid in several neurodegenerative diseases. However, evidence is still lacking to firmly establish whether exercise constitutes a practical neuroprotective strategy. We now show that exercise provides a remarkable protection against brain insults of different etiology and anatomy. Laboratory rodents were submitted to treadmill running (1 km/d) either before or after neurotoxin insult of the hippocampus (domoic acid) or the brainstem (3-acetylpyridine) or along progression of inherited neurodegeneration affecting the cerebellum (Purkinje cell degeneration). In all cases, animals show recovery of behavioral performance compared with sedentary ones, i.e., intact spatial memory in hippocampal-injured mice, and normal or near to normal motor coordination in brainstem-and cerebellum-damaged animals. Furthermore, exercise blocked neuronal impairment or loss in all types of injuries. Because circulating insulin-like growth factor I (IGF-I), a potent neurotrophic hormone, mediates many of the effects of exercise on the brain, we determined whether neuroprotection by exercise is mediated by IGF-I. Indeed, subcutaneous administration of a blocking anti-IGF-I antibody to exercising animals to inhibit exercise-induced brain uptake of IGF-I abrogates the protective effects of exercise in all types of lesions; antibodytreated animals showed sedentary-like brain damage. These results indicate that exercise prevents and protects from brain damage through increased uptake of circulating IGF-I by the brain. The practice of physical exercise is thus strongly recommended as a preventive measure against neuronal demise. These findings also support the use of IGF-I as a therapeutical aid in brain diseases coursing with either acute or progressive neuronal death.

Insulin-like growth factor I is required for vessel remodeling in the adult brain

“…As shown in detail before, this treatment effectively blocks IGF-I input to the target cells within the brain (9). Under these conditions, early activation of HIF-1␣ and VEGF in the perilesion area was significantly attenuated (Fig.…”

“…Animals were allowed to survive for 1, 3, 14, or 28 days. In a separate set of experiments, brain-injured LID mice received a s.c. infusion of a blocking anti-IGF-I over 28 days, as described elsewhere (9). Control groups of injured LID mice were infused with either nonimmune rabbit serum (NRS) or vehicle (saline).…”

“…The beneficial effects of exercise on the brain are blocked when the serum IGF-I input to the brain is reduced (9,10,19). To determine whether the angiogenic response to exercise is also modulated by circulating IGF-I, we examined exercise-induced angiogenesis in mice that had normal levels of IGF-I in the brain (95% of the levels of control littermates, n ϭ 6), but greatly reduced levels in serum [LID mice, (11)].…”

Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction

“…34 Also, the neuroprotective effect of physical exercise in rodent models of ataxia, domoic acid-mediated hippocampal damage and inherited Purkinje cell degeneration (pcd mouse model) was reported to be mediated by circulating IGF-I. 35 Our morphometric data show an increase in TH+ neurons in the hypothalamus of senile rats treated with RAd-IGFI. This increase could be accounted for by a trophic effect of transgenic IGF-I on pre-existing dysfunctional DA neurons expressing low levels of TH (putative THÀ DA neurons), which would be rendered TH+ by the treatment.…”

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

“…However, other animal studies reveal that repeated running with defined intensity and duration improves the motor function and prevents the decay of Purkinje cells under various pathological conditions. For example, chronic treadmill exercise improves motor performance and protects Purkinje cells from degeneration in ataxia animal models (3,29). Additionally, chronic treadmill running in young rats prevents Purkinje cell loss from traumatic brain injury (27).…”