The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central ...nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.
Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell ...homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.
Abstract
The nerve growth factor (NGF) belongs to a family of neurotrophic factors called neurotrophins. It was discovered as a molecule that stimulates the survival and maturation of developing ...neurons in the peripheral nervous system and has later been shown to protect adult neurons in the degenerating mammalian brain. Basic and clinical studies have been undertaken to use NGF as a therapeutic agent aimed at restoring and maintaining neuronal function in the central nervous system and to determine the mechanisms to safely deliver the molecule into the brain. Recent studies have also recognized that the role of NGF extends far beyond the horizon of nerve cells and even beyond the peripheral and central nervous system. Studies published from our laboratory have shown that topical application of NGF possesses a protective action on human pressure ulcer, corneal ulcer and glaucoma. Here, we will review these studies, supporting the therapeutic potential of NGF.
We aimed to evaluate the nerve growth factor (NGF) pathway and its influence on corneal healing mechanisms in normal conditions and in an animal model of corneal denervation induced by capsaicin.
...Peripheral sensory damage was induced in rat pups by subcutaneous injection of capsaicin and the effects evaluated by hot-plate test, corneal nerve count, and tear secretion. Corneal damage was induced in capsaicin-treated and -untreated rats by epithelial scraping. Healing rate; NGF pathway (NGF, tyrosine kinase A TrkA, p75); and the stem cell marker p63 were evaluated by RT-PCR, ELISA, Western blot, and immunohistochemistry. The effects of exogenous NGF administration as eye drop formulation were also tested.
Capsaicin treatment induced a significant reduction of peripheral sensitivity, corneal innervation, tear secretion, and corneal healing rate. The ocular effects of capsaicin treatment were associated with an NGF pathway alteration. NGF eye drop treatment aided corneal healing mechanisms through a significant increase in the NGF receptors TrkA and p75, and in the stem cell marker p63.
In this study, we show that an alteration in the NGF pathway is responsible for a delay in corneal healing in an animal model of sensory denervation. Moreover, we show that NGF eye drop administration modulates corneal innervation, epithelial cell healing, and corneal stem cells. These findings may trigger further research on the role of the NGF pathway in limbal stem cell deficiency.
Down syndrome, a genetic condition caused by triplication of chromosome 21, is characterized by widespread neurogenesis reduction and cognitive impairment. Unlike other brain functions, smell is not ...impaired at early life stages and olfactory deterioration begins to appear in adulthood. Similarly to individuals with Down syndrome, in the Ts65Dn mouse model of Down syndrome smell function is normal at early life stages. Smell impairment only appears in adulthood associated with a reduction in the number of new granule neurons migrated to the olfactory bulb from the subventricular zone. Based on evidence that lithium positively impacts neurogenesis, the goal of current study was to establish whether treatment with lithium restores olfactory bulb neurogenesis and olfactory performance in middle-aged Ts65Dn mice.
Euploid and Ts65Dn mice aged 13 months were treated with lithium chow or control chow for one month. Before the end of treatment, mice were injected with BrdU, in order to label proliferating cells. Results showed that in Ts65Dn mice lithium treatment restored the number of neural precursor cells in the subventricular zone of the lateral ventricle, rostral migratory stream and olfactory bulb. This effect was accompanied by restoration of olfactory performance. Unlike in olfactory neurogenic regions, treatment had no neurogenesis-enhancing effect on the subgranular zone of the hippocampal dentate gyrus, indicating that lithium has no generalized positive effect on the brain.
Results suggest that lithium may have a positive impact in brain disorders that, similarly to Down syndrome, are characterized by olfactory decline and neurogenesis impairment in the subventricular zone.
Respiratory dysfunction is among the main cause of severe and fatal pathologies worldwide. The use of effective experimental models and methodologies for the study of the pulmonary pathophysiology is ...necessary to prevent, control and cure these diseases. Plethysmography, a technique for the assessment of lung function, has been widely applied in mice for the characterization of respiratory physiology. However, classical plethysmography methods present technical limitations such as the use of anesthesia and animal immobilization. Whole-body plethysmography (WBP) avoids these issues providing a non-invasive approach for the assessment of the respiratory function in conscious animals. WBP relies on the recording of pressure changes that are produced by the spontaneous breathing activity of an animal placed inside an airtight chamber. During normal respiration, pressure variation is directly proportional to the respiratory pattern of the animal allowing the measurement of the respiratory rate and tidal volume. These parameters are commonly used to evaluate pulmonary function in different physiological and disease models. In contrast to classical plethysmography methods, WBP technique allows reproducible serial measurements as it avoids animal restraint or the use of anesthesia. These key features rend WBP a suitable approach for longitudinal studies allowing the assessment of progressive respiratory alterations in physiological and pathological conditions. This protocol describes the procedures for the measurement of the breathing patterns in mice using the WBP method, the data analysis and results interpretation.
The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such ...therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.
Down syndrome (DS), a high‐incidence genetic pathology, involves brain hypoplasia and mental retardation. Emerging evidence suggests that reduced neurogenesis may be a major determinant of brain ...underdevelopment in DS. To establish whether it is possible to improve neurogenesis in DS, Ts65Dn mice—the most widely used model for DS—and euploid mice were treated with control or lithium chow for 1 month. During the last 3 days animals received one daily injection of 5‐bromo‐2‐deoxyuridine (BrdU)—a marker of proliferating cells—and were sacrificed 24 h after the last injection. Neurogenesis was examined in the subventricular zone (SVZ), a region that retains a neurogenic potential across life. We found that Ts65Dn mice had less (−40%) BrdU+ cells than euploid mice, indicating severe proliferation impairment. Treatment with lithium increased the number of Brdu+ cells in both euploid and Ts65Dn mice. In the latter the number of Brdu+ cells became similar to that of untreated euploid mice. Our study shows that lithium is able to restore cell proliferation in the SVZ of the Ts65Dn mouse and point at treatments with mood stabilizers as a potential tool to improve neurogenesis in patients with DS.
The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions ...crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
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