Neurotrophic and Neuroregenerative Effects of GH/IGF1

Human neurodegenerative diseases, such as ALS [ 1 ], Alzheimer’s [ 2 ], Parkinson’s disease [ 3 ], and prion disorders, are related to the aging process, and represent a constant increasing economic and social burden for modern society. Maintenance of the efficiency of CNS is particularly important in aging and for the control of metabolism. The GH/IGF-1 axis plays the main role in brain growth, development, and myelination, but also in the neurogenesis process and plasticity [ 4 ]. It is a difficult task to distinguish between the effects of GH from IGF-1, due to the half-life of GH in plasma and to the cross-activation of receptors. Both GH and IGF-I can cross from the blood to the brain by physiological mechanisms [ 5 , 6 ]. IGF-1 may get in the brain parenchyma capillaries through the blood brain barrier, and they may be filtered through the choroid plexus into the cerebrospinal fluid [ 6 ]. Furthermore, IGF-1 sustains the brain through the activation of IGF-II gene expression, as well as by uptake into the cerebrospinal fluid [ 7 ]. Experimental models in animals showed that GH is absorbed via the capillary of blood brain barrier, supporting the concept that GH influx happens by simple diffusion, although a specific transport system has not been demonstrated [ 5 ]. GH/IGF-1 are determinant regulators of cellular function, and an impaired release of GH and IGF-1 with advancing age leads to severe alterations in tissue structures and functions, especially within the brain [ 8 ]. GH is secreted by the anterior pituitary gland, and the primary effect is the activation of GH receptors and the secretion of IGF-1, mainly by the liver [ 9 ], and locally by the brain [ 10 ]. The effects of GH are mediated by the transmembrane GH receptors, which are expressed on the surface of most cells [ 11 ]. Therefore, GH acts through two independent mechanisms of action: one activating the cellular GH receptors, and the other inducing the IGF1 secretion by the liver. Insulin-like growth factors (IGFs) are transported in the blood by six binding proteins, IGF-BP1–6, and IGF-1 is transported mainly by IGF-BP3 [ 12 ]. At the CNS level, a high expression of GH and IGF-1 receptors has been shown [ 13 , 14 ], suggesting that brain cells, such as neurons, glia, and oligodendrocytes, actively respond to GH and IGF-1 signaling. Pulses of GH and IGF-1 increased significantly only around adolescence, and the amplitude of GH releases increases the level of circulating IGF-1. The decline of GH secretion [ 15 ] results in a decrease in circulating IGF-1 levels [ 16 ]. IGF-1 can also be synthesized within the cerebral and peripheral nerve cells, with the purpose of stimulating the development and growth of neurons and glial cells [ 17 ]. GH can act directly on the brain, by activating GH receptors located on the membrane of the cerebral cortex neurons, on neurons of the thalamus and hypothalamus, on Purkinje cells of the cerebellum, on neurons of the trapezoid body of the brainstem, and on retinal ganglion cells [ 14 ]. In embryonic cultures from cerebral cortex, it was demonstrated that GH stimulated neuronal precursor and glial cells [ 18 , 19 ], increased neurogenesis, myelination, and synaptogenesis, [ 4 ]. These effects of GH are mediated by the local production of IGF-1 and IGF-BP3 [ 18 ]. In adults, GH administration regulates brain function, learning, memory, and neuroprotection [ 20 ]. Glial cells, including microglia, astrocytes, and oligodendrocyte lineage cells, are also strongly reactive to GH [ 14 , 21 ]. GH deficiency in mouse causes the reduction in oligodendroglial cells and the myelination process [ 22 ]. Astrocytes, which are the most abundant and well-studied type of glial cell in the adult brain [ 23 ], play a crucial role in the maintenance of brain health, protecting it by inflammation [ 24 ]. GH, when administered intravenous (iv), exerts its effect on astrocytes, and seems to mediated by the PI3K/Akt pathway [ 25 ]. Oligodendrocytes are responsible for the myelin production in axons, and gives them trophic support, ensuring long-term integrity [ 26 ]. Loss of myelin is responsible of various neurological diseases, and contributes to neuropsychiatric disorders. Glial cells are involved in providing neurotrophic signals to neurons required for their survival, proliferation, and differentiation. Furthermore, it is recognized that glial cells have some effects on certain physiological processes, such as breathing, and in assisting neurons to form synaptic connections amongst one another [ 27 ]. Astrocytes maintain the homeostatic environment of the CNS and play an important role in immune regulation, acting a source of chemokines, cytokines, and effector molecules [ 28 ]. Growth factors (GFs) typically act as signaling molecules between cells [ 29 ]. They perform an essential function in the route of signaling molecules between astrocytes and neurons [ 30 ]. GH-induced neuroprotection downregulating the apoptosis-pro

Of the retrieved articles, we selected eight articles on the effect of GH in patients who suffered from traumatic brain injury (TBI), enrolling 1140 patients with a mean age of 41.0 ± 10.6 ( Table 1 ). Six studies on the effect of GH and IGF-1 in patients with ALS, enrolling 741 patients with a mean age of 53.2 ± 5.42 years ( Table 2 ). One study evaluated the effect of GHRH (growth hormone releasing hormone) in patients with AD. The neuroregenerative effect of GH and IGF1 on peripheral nerve regeneration (PNF) has been considered, although no clinical studies in human have been found. While the administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function, IGF-1and GH therapy in ALS evidenced some contradictory results. The data are summarized in the flow chart (see Figure 1 ). 3.1. Mechanisms of Action IGF-1 has a high affinity for its receptor, a tyrosine kinase receptor which mediates PI3K-AKT. Akt is a critical mediator of growth factor-induced neuronal survival [ 55 ]. Brain IGF-1 signaling has a major inhibitor of GSK3β, activating anabolic and neuroprotective effects [ 56 ]. The MAP kinase pathways play a fundamental role in neuronal tropism and survival, and prevent neuronal apoptosis [ 57 , 58 ]. Additional pathways linked to IGF-I signaling include the JNK, p38 MAPK, and mTOR signaling pathways. The mitogen-activated protein kinase (MAP-kinase) pathway is activated by many extracellular stimuli, and exerts a fundamental role in human pathology. Its inhibition (obtained by removing particular JNK genes) reduces the severity of various diseases, including Parkinson’s disease and cerebral ischemia [ 59 ]. Inhibitors of JNK have been used as a therapeutic strategy for neuroprotection in the retina [ 60 ], and multitargeting inhibitor protein kinases have been proposed as the most promising strategy to treat Alzheimer’s disease [ 61 ]. The growth factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and IGF-1. Trophic factors exert their mechanism of action, stimulating the motor neuron function and survival, and may have a potential therapeutic activity on clinical outcome of various neurologic disorders [ 62 ]. High IGF-1 level protects against β-amyloid deposition, and the insulin/IGF-1 signaling pathway shows a neuroprotective action [ 63 ]. The infusion of IGF-1 in the brain of old rats cleared the β-amyloid deposition reaching the level of young animals [ 64 ], while the reduction of serum IGF-1 level in AD animal model accelerated the deposition of β-amyloid plaques in the brain [ 65 ]. Insulin is the main stimulator of β-amyloid release by neurons [ 66 ], also observed in older subjects [ 67 ]. However, IGF-1 activating insulin receptors can stimulate β-amyloid deposition also. Insulin/IGF-1 signaling is extremely important in the control of neurogenesis [ 68 ], because it can regulate neural, stem cell proliferation, differentiation, and survival [ 69 ]. Astrocytes have a different susceptibility compared with neurons to insulin/IGF-1 activity. Insulin receptor in the nucleus has a variable range of expression at a molecular level, suggesting that the signaling is not limited to the cytoplasm [ 70 ]. A reduced insulin/IGF-1 signaling in experimental animal model protects the mammalian brain from amyloid-β toxic effects, neurodegeneration, and Alzheimer disease [ 71 ]. Similar results have been obtained by providing adenoviral administration of IGF-1 [ 72 ], and reducing IGF-1 signaling [ 73 ]. However, whether IGF-1 signaling is protecting the mammalian brain is still under discussion. Reducing insulin/IGF-1 signaling alters the aging process [ 36 , 44 ], and the major risk factor for the development of neurodegeneration is aging [ 74 ]. Thus, reducing rather than increasing IGF-1 signaling should ameliorate aging-associated diseases. Gontier et al. [ 71 ] demonstrated in a mouse model that the progression of the AD is significantly delayed when IGF signaling is blocked. In experimental AD animal models, a less abundant deposition of β-amyloid and reduction of neuroinflammation was observed. Also, increased β-amyloid load and plaque formation were considered, in many studies, as a marker of toxicity [ 65 , 75 ]. A conflict arises because reduced insulin/IGF-1 signaling in the CNS is associated with longevity, but can dysregulate glucose and energy homeostasis, and promote being overweight. White et al. [ 76 ] have explored how the genetic manipulation of insulin/IGF-1 signaling system could influence systemic metabolism, lifespan, and neurodegeneration. In the complex mechanism of insulin/IGF-1 signaling on the neuron, the interaction with other factors, such as sex hormones and nutrition, to regulate nutrient homeostasis, should be considered [ 69 , 77 ]. The insulin/IGF-1 signaling effect on ne

ALS is a disease of the nervous system, characterized by degeneration of both upper and lower motor neurons of the spinal cord, brainstem, and cortex [ 94 ]. The disease causes frontotemporal dementia, progressive muscle and strength loss, dysphagia, dyspnea, and progressively, death [ 95 ]. ALS and frontotemporal dementia are different diseases with similar clinical and pathological conditions [ 96 ], but the pathogenesis of motoneuron degeneration is not yet entirely understood. ALS has familial transmission of 20–25%, with clinical evolution similar to sporadic ALS [ 97 ]. Swedish and UK studies evaluated the incidence of heritability of 61% [ 98 ]. ALS was characterized by mutations in the gene for superoxide dismutase-1 (SOD1) [ 99 ], with an incidence of 10–20% of ALS patients and 1–2% in sporadic ALS [ 100 ]. More than 100 type SOD1 mutations that cause ALS are known [ 97 ]. Steyn et al. [ 101 ] found in male mice, genetically hSOD1(G93A), had a reduced pulsatile secretion of GH and a decreased plasma IGF-1 level, and reduced IGF-1 receptor expression at muscular and lumbar spinal cord levels. Interestingly, the alterations in GH and IGF-1 secretions in these mice have been found in 50–70% of human patients with ALS [ 102 , 103 ]. These data demonstrated a correlation between GH deficiency and hSOD1(G93A) expression, and are essential for the consideration of GH and IGF-1 therapy in ALS. Other proposed mechanisms in ALS pathogenesis are glutamate-induced neurotoxicity with increased glutamate concentration in cerebrospinal fluid [ 104 ], and altered oxidative stress reactions, protein and DNA damage, alterations in axonal transport, and dysregulated autophagy [ 105 ]. Saenger et al. [ 106 ] investigated the effect of IGF-1 in two SOD1-G93A mouse lines that express a pathology similar to familial ALS (the milder and the more severe phenotype form). Results showed that in a milder form, pegylated-IGF-1 treatment, significantly improved muscle force, motor coordination, and animal survival. In contrast, treatment of more severe form with pegylated-IGF-1 or IGF-1, even at high doses, did not increase survival or functional outcomes, despite increased signaling in the brain and spinal cord by both agents. These findings show that IGF-1 treatment can be effective only in milder forms of ALS, or when the efficiency of the neuron is still preserved. The functional improvement induced by IGF-1 treatment is dependent on the severity of disease [ 106 ]. The protective effect of GH in familial ALS has been demonstrated in both in vitro and in vivo models [ 107 ]. In patients with ALS, a significant reduction of GH secretion was found with higer incidence in male than in women, 83% versus 60%, respectively [ 102 ]. The plasma IGF-1 level is also reduced, suggesting an involvement of the GH/IGF-I axis in the development of ALS [ 108 ]. Only two studies evaluated the effect of GH therapy in ALS human subjects. Smith et al. [ 109 ] found that in 75 patients with ALS, that 18 month GH administration did not determine any clinical improvement in the treatment group, compared with controls. The poor prognosis was more severe in patients with early loss of muscular strength, indicating that GH therapy had been ineffective on motor neuron function. Similar results were found by Saccà et al. [ 84 ], that demonstrated no beneficial effect on neuronal loss, and motor function in patients with ALS treated with GH. The evaluation of the upper motoneuron loss had been determined with magnetic resonance spectroscopy. Kaspar et al. [ 110 ] showed that GH therapy associated with exercise might exert a synergistic effect. Lunetta et al. [ 111 ] described motor neuron degeneration in ALS disease due to an abnormal expression of IGF-1 in the skeletal muscle, suggesting that IGF-1 expression in muscular tissue is essential to maintain the motor neuron efficiency. In our search, we retrieved only four clinical studies, reporting the effect of IGF-1 administration in ALS [ 112 , 113 , 114 , 115 ], and two on GH effects in ALS [ 84 , 109 ], see Table 2 . Lai et al. [ 115 ] published a study conducted in 266 patients, treated in the USA with two different doses (0.05 and 0.10 mg/kg/day) by subcutaneous administration of rhIGF-I. The treatment led to a 26% deceleration in functional impairment compared to placebo-treated patients. High and low doses produced similar effects. Borasio et al. [ 114 ] conducted a similar placebo-controlled trial study in 183 ALS patients, from 8 European countries, receiving for nine months, rhIGF-1, 0.10 mg/kg/day subcutaneously, and did not find any significant difference among groups. Both studies used a similar dose of therapy and endpoints (disease progression assessed by the Appel ALS rating scale), and found that rhIGF-I was safe and well-tolerated. The analysis of the data derived from both studies showed a significant benefit to high-dose rhIGF-I treatment on the primary clinical outcome [ 116 ]. No

AD is a form of neurodegenerative disease accounting for 50–70% of all causes of cognitive impairment [ 134 ], and is strongly correlated to amyloid-β (Aβ) deposition, causing the neurodegeneration [ 135 ]. Many risk factors are implicated in the pathogenesis of AD, and cognitive impairment remains the primary focus of prevention [ 136 ]. A recent review on clinical studies of mild to moderate dementia cases showed no real progress in identifying disease-modifying treatments [ 137 ]. Diet and antioxidant deficiencies have been proposed [ 138 ]. However, a large population study, aimed at evaluating the effect of the supplemental use of vitamin E and selenium to prevent dementia, showed that these antioxidants did not forestall dementia, and are not recommended as preventive agents [ 139 ]. In AD pathogenesis, both estrogens and androgens have been implicated because they exert a wide range of protective actions on brain structures [ 140 ]. Low testosterone level in the brain is correlated with AD incidence, and inversely correlated with β-amyloid deposition in men [ 141 ], while in female, 17β-estradiol has a protective effect against AD [ 142 ]. In patients affected by AD, the GH/IGF-1 axis is downregulated [ 143 ], and in particular, IGF-1 therapies could provide significant benefits to these patients [ 144 ]. Inflammation plays an important role in the pathogenesis of AD, and represents the predominant mechanism of activation and progression of the disease [ 145 ]. High serum level of pro-inflammatory cytokines anticipates the detection of β-amyloid in the brain [ 146 ], suggesting that they can stimulate amyloid precursors [ 147 ] and drive AD development [ 148 ]. Inflammation in the brain occurs early, and is evident also in the preclinical condition of the AD, favouring the development of the pathology [ 149 ]. An inverse correlation between inflammatory processes with the level of sex steroids has been observed and reviewed by Uchoa et al. [ 150 ]. Friedman et al. [ 151 ] evaluated the effect of the growth hormone-releasing hormone (GHRH) analog, tesamorelin (1 mg/day, for 20 weeks), on 30 adults with a mean age ranging from 55 to 87 years. They found increased GABA levels in all three brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal), increased N -acetylaspartylglutamate levels in the frontal cortex, and decreased myoinositol concentrations in the posterior cingulate, which are linked to the AD. The study demonstrated a favorable effect of GHRH administration in adult patients with mild cognitive impairment, independent of the IGF-1 level that did not change significantly. The neuronal defenses against AD rely on a neuroprotective response activated by genetic disruption of IGF1R signaling. George et al. [ 152 ] evidenced the neuronal IGF1R signaling as a relevant target to prevent AD. McGinley et al. [ 144 ] generated human cortical neural stem cells that stably produced IGF-1, and were then transplanted into double-transgenic mice, a model used for AD. These novel human cortex-derived cells preferentially differentiated into gamma-aminobutyric acidergic neurons, a subtype of dysregulated neuron in AD, produced an increase of vascular endothelial growth factor levels, and display an increased neuroprotective capacity in vitro. The authors found a significantly reduced level of death. This supports the idea that IGF-1 provides an increased protection of spinal cord neural stem cells to cellular insults, and could represent a model for a future therapeutic strategy for AD. Nowadays, no clinical studies have evaluated the effect of GH/IGF-1 in the prevention and treatment of patients with AD.

GH and IGF-1 play a fundamental role in growth and maintenance of CNS and PNS, and a positive effect on clinical outcome has been observed in TBI patients. However, lack of clinical studies in human subjects about the effects of exogenous administration of GH and IGF-1, and the evolution of neurodegenerative diseases, make it difficult to draw conclusions. The positive effects of IGF-1 therapy in ALS patients are limited, and probably due to the advanced state of the inflammatory process and pathologic alteration in neurons, so that their survival is severely compromised or irreversible. The level of severity of the disease can suggest that, when neurons are deeply damaged, functional recovery is impossible Treatment should be started as a preventive therapy in the first stages of neurological disease. The efficacy of GH/IGF-1 therapy is related to the plasma level of sex hormones, such as testosterone and estradiol. Furthermore, nutrition and physical activity also play an important role. However, against our conclusions, one of the major critical arguments is the longevity-related low IGF-1 levels found in nonagenarians [ 222 ], but of course, we do not know the central nervous activity of the IGF-1 receptors and all the other hormones possibly involved in neuroprotection. More specific clinical trials are necessary to evaluate the potential therapeutic effect of GH and IGF-1 on the brain, considering also sex hormones, nutrition, and physical exercise.