Although the physiological significance of continued formation of new neurons in the adult mammalian brain is still uncertain, therapeutic strategies aimed to potentiate this process show great promise. Several external factors, including physical exercise, increase the number of new neurons in the adult hippocampus, but underlying mechanisms are not yet known. We recently found that exercise stimulates uptake of the neurotrophic factor insulin-like growth factor I (IGF-I) from the bloodstream into specific brain areas, including the hippocampus. In addition, IGF-I participates in the effects of exercise on hippocampal c-fos expression and mimics several other effects of exercise on brain function. Because subcutaneous administration of IGF-I to sedentary adult rats markedly increases the number of new neurons in the hippocampus, we hypothesized that exercise-induced brain uptake of blood-borne IGF-I could mediate the stimulatory effects of exercise on the adult hippocampus. Thus, we blocked the entrance of circulating IGF-I into the brain by subcutaneous infusion of a blocking IGF-I antiserum to rats undergoing exercise training. The resulting inhibition of brain uptake of IGF-I was paralleled by complete inhibition of exercise-induced increases in the number of new neurons in the hippocampus. Exercising rats receiving an infusion of nonblocking serum showed normal increases in the number of new hippocampal neurons after exercise. Thus, increased uptake of blood-borne IGF-I is necessary for the stimulatory effects of exercise on the number of new granule cells in the adult hippocampus. Taken together with previous results, we conclude that circulating IGF-I is an important determinant of exercise-induced changes in the adult brain.

Physical exercise increases brain activity through mechanisms not yet known. We now report that in rats, running induces uptake of blood insulin-like growth factor I (IGF-I) by specific groups of neurons throughout the brain. Neurons accumulating IGF-I show increased spontaneous firing and a protracted increase in sensitivity to afferent stimulation. Furthermore, systemic injection of IGF-I mimicked the effects of exercise in the brain. Thus, brain uptake of IGF-I after either intracarotid injection or after exercise elicited the same pattern of neuronal accumulation of IGF-I, an identical widespread increase in neuronal c-Fos, and a similar stimulation of hippocampal brain-derived neurotrophic factor. When uptake of IGF-I by brain cells was blocked, the exercise-induced increase on c-Fos expression was also blocked. We conclude that serum IGF-I mediates activational effects of exercise in the brain. Thus, stimulation of the uptake of blood-borne IGF-I by nerve cells may lead to novel neuroprotective strategies.

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; antibody-treated 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.

Background: Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods: We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) uptake by positron emission tomography (PET). Results: Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased ¹⁸FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro. Conclusions: In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

The involvement of circulating insulin-like growth factor I (IGF-I) in the beneficial effects of physical exercise on the brain makes this abundant serum growth factor a physiologically relevant neuroprotective signal. However, the mechanisms underlying neuroprotection by serum IGF-I remain primarily unknown. Among many other neuroprotective actions, IGF-I enhances clearance of brain amyloid β (Aβ) by modulating transport/production of Aβ carriers at the blood-brain interface in the choroid plexus. We found that physical exercise increases the levels of the choroid plexus endocytic receptor megalin/low-density lipoprotein receptor-related protein-2 (LRP2), a multicargo transporter known to participate in brain uptake of Aβ carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of Aβ and is involved in IGF-I transport into the brain. Through this dual role, megalin participates in the neuroprotective actions of IGF-I including prevention of tau hyperphosphorylation and maintenance of cognitive function in a variety of animal models of cognitive loss. Because we found that in normal aged animals, choroid plexus megalin/LRP2 is decreased, an attenuated IGF-I/megalin input may contribute to increased risk of neurodegeneration, including late-onset Alzheimer's disease.