Regional brain susceptibility to neurodegeneration: what is the role of glial cells?

The main pathological feature of the neurodegenerative diseases is represented by neuronal death that represents the final step of a cascade of adverse/hostile events. Early in the neurodegenerative process, glial cells (including astrocytes, microglial cells, and oligodendrocytes) activate and trigger an insidious neuroinflammatory reaction, metabolic decay, blood brain barrier dysfunction and energy impairment, boosting neuronal death. How these mechanisms might induce selective neuronal death in specific brain areas are far from being elucidated. The last two decades of neurobiological studies have provided evidence of the main role of glial cells in most of the processes of the central nervous system, from development to synaptogenesis, neuronal homeostasis and integration into, highly specific neuro-glial networks. In this mini-review, we moved from in vitro and in vivo models of neurodegeneration to analyze the putative role of glial cells in the early mechanisms of neurodegeneration. We report changes of transcriptional, genetic, morphological, and metabolic activity in astrocytes and microglial cells in specific brain areas before neuronal degeneration, providing evidence in experimental models of neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Understanding these mechanisms might increase the insight of these processes and pave the way for new specific glia-targeted therapeutic strategies for neurodegenerative disorders.

Loss of TrkB Signaling Due to Status Epilepticus Induces a proBDNF-Dependent Cell Death.

Neurotrophins (NTs) are secretory proteins that bind to target receptors and influence many cellular functions, such as cell survival and cell death in neurons. The mammalian NT brain-derived neurotrophic factor (matBDNF) is the C-terminal mature form released by cleavage from the proBDNF precursor. The binding of matBDNF to the tyrosine kinase receptor B (TrkB) activates different signaling cascades and leads to neuron survival and plasticity, while the interaction of proBDNF with the p75 NT receptor (p75NTR)/sortilin receptor complex has been highly involved in apoptosis. Many studies have demonstrated that prolonged seizures such as status epilepticus (SE) induce changes in the expression of NT, pro-NT, and their receptors. We have previously described that the blockage of both matBDNF and proBDNF signaling reduces neuronal death after SE in vivo (Unsain et al., 2008). We used an in vitro model as well as an in vivo model of SE to determine the specific role of TrkB and proBDNF signaling during neuronal cell death. We found that the matBDNF sequestering molecule TrkB-Fc induced an increase in neuronal death in both models of SE, and it also prevented a decrease in TrkB levels. Moreover, SE triggered the interaction between proBDNF and p75NTR, which was not altered by sequestering matBDNF. The intra-hippocampal administration of TrkB-Fc, combined with an antibody against proBDNF, prevented neuronal degeneration. In addition, we demonstrated that proBDNF binding to p75NTR exacerbates neuronal death when matBDNF signaling is impaired through TrkB. Our results indicated that both the mature and the precursor forms of BDNF may have opposite effects depending on the scenario in which they function and the signaling pathways they activate.

Brain-region specific responses of astrocytes to an in vitro injury and neurotrophins.

Astrocytes are a heterogeneous population of glial cells that react to brain insults through a process referred to as astrogliosis. Reactive astrocytes are characterized by an increase in proliferation, size, migration to the injured zone and release of a plethora of chemical mediators such as NGF and BDNF. The aim of this study was to determine whether there are brain region-associated responses of astrocytes to an injury and to the neurotrophins NGF and BDNF. We used the scratch injury model to study the closure of a wound inflicted on a monolayer of astrocytes obtained from cortex, hippocampus or striatum. Our results indicate that the response of astrocytes to a mechanical lesion differ according to brain regions. Astrocytes from the striatum proliferate and repopulate the injury site more rapidly than astrocytes from cortex or hippocampus. We found that the scratch injury induced the upregulation of neurotrophin receptor p75NTR and TrkB.t in astrocytes from all brain regions studied. When astrocytes from all regions were treated with NGF, the neurotrophin induced migration of the astrocytes (assessed in Boyden chambers) and induced wound closure but did not affect proliferation. In contrast, BDNF induced wound closure but only in astrocytes from striatum. Our overall findings show the heterogeneity in astrocyte functions based on their brain region of origin, and how this functional diversity may determine their responses to an injury and to neurotrophins.

Interleukin-1 beta-induced anorexia is reversed by ghrelin.

Interleukins, in particular interleukin-1beta (IL-1beta), reduce food intake after peripheral and central administration, which suggests that they contribute to anorexia during various infectious, neoplastic, and autoimmune diseases. On the other hand, ghrelin stimulates food intake by acting on the central nervous system (CNS) and is considered an important regulator of food intake in both rodents and humans. In the present study, we investigated if ghrelin could reverse IL-1beta-induced anorexia. Intracerebroventricular (i.c.v.) injection of 15, 30 or 45 ng/microl of IL-1beta caused significant suppression of food intake in 20 h fasting animals. This effect lasted for a 24h period. Ghrelin (0.15 nmol or 1.5 nmol/microl) produced a significant increase in cumulative food intake in normally fed animals. However, it did not alter food intake in 20 h fasting animals. Central administration of ghrelin reduced the anorexic effect of IL-1beta (15 ng/microl). The effect was observed 30 min after injection and lasted for the next 24h. This study provides evidence that ghrelin is an orexigenic peptide capable of antagonizing IL-1beta-induced anorexia.

Alpha-MSH and gamma-MSH modulate early release of hypothalamic PGE2 and NO induced by IL-1beta differently.

Interleukin-1beta (IL-1beta) stimulates corticotropin-releasing hormone (CRH) secretion in hypothalamus, which involves the release of prostaglandins (PGE2) and nitric oxide (NO). We have demonstrated that melanocortins can inhibit the early effects of IL-1beta on the HPA axis by acting on the central nervous system (CNS). Our study investigated whether alpha-melanocyte stimulating hormone (alpha-MSH) and gamma-MSH could inhibit IL-1beta-induced PGE2 and NO release in hypothalamus in the rapid activation of the HPA axis. An i.c.v. injection of 12.5 ng/microl of IL-1beta significantly increased the release of PGE2 and NOS activity in the hypothalamus. Treatment with alpha-MSH (0.1 microg/microl) inhibited the effect of IL-1beta on PGE2 release. Also, gamma-MSH (1 microg/microl) eliminated the increase in NOS activity induced by IL-1beta. Our data indicate the modulatory role of melanocortins in the early hypothalamic response to IL-1beta, with different regulation of PGE2 and NO release.

Anxiety-like behavior induced by IL-1beta is modulated by alpha-MSH through central melanocortin-4 receptors.

The proinflammatory cytokine interleukin-1beta (IL-1beta) influences neuroendocrine activity and produces other effects, including fever and behavioral changes such as anxiety. The melanocortin neuropeptides, such as alpha-melanocyte-stimulating hormone (alpha-MSH), antagonize many actions of IL-1, including fever, anorexia and hypothalamic-pituitary-adrenal (HPA) axis activation through specific melanocortin receptors (MC-R) in the central nervous system. The objective of the present study was to establish the effect of MSH peptides on IL-1beta-induced anxiety-like behavior and the melanocortin receptors involved. We evaluated the effects of intracerebroventricular (i.c.v.) administration of IL-1beta (30 ng) and melanocortin receptor agonists: alpha-MSH, an MC3/MC4-R agonist (0.2 microg) or gamma-MSH, an MC3-R agonist (2 microg) or HS014, an MC4-R antagonist (2 microg), on an elevated plus-maze (EPM) test. Injection of IL-1beta induced an anxiogenic-like response, as indicated by reduced open arms entries and time spent on open arms. The administration of alpha-MSH reversed IL-1beta-induced anxiety with co-administration of HS014 inhibiting the effect of alpha-MSH. However, the associated treatment with gamma-MSH did not affect the anxiety response to IL-1beta. These data suggest that alpha-MSH, through central MC4-R can modulate the anxiety-like behavior induced by IL-1beta.

alpha-MSH and gamma-MSH inhibit IL-1beta induced activation of the hypothalamic-pituitary-adrenal axis through central melanocortin receptors.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuroimmunomodulatory peptide that is involved in the control of host responses trough modulation of production and action of proinflammatory cytokines in inflammatory cells in the periphery and within the central nervous system (CNS). However, little is known about the receptors that mediate the modulatory effects of alpha-MSH in the CNS. The objective of the present study was to establish the specific melanocortin receptors involved in the inhibition by MSH peptides of IL-1beta-induced activation of the HPA. i.c.v. injection of 12.5 ng of IL-1beta caused significant changes in plasma corticosterone, as compared to basal levels. The treatment with gamma-MSH (1 microg), an MC3 receptor agonist, resulted in significant reduction of the IL-1beta-induced plasma corticosterone levels. Administration of the MC3/MC4 receptor antagonist SHU9119 blocked this effect. Besides, treatment with a high dose of alpha-MSH (1 microg) increased plasma corticosterone. When alpha-MSH was given at a lower dose (0.1 microg), it did not modify corticosterone levels but caused an inhibitory effect on the corticosterone release induced by IL-1beta. The administration of SHU9119 or a more selective MC4 receptor antagonist like HS014 blocked the effects of alpha-MSH. In conclusion, our results suggest that both alpha-MSH and gamma-MSH are capable of inhibiting the effect of the IL-1beta on the activation of HPA axis acting at the CNS, and that this effect is mediated by specific central melanocortin receptors.