Neurotrophic factors and diabetic peripheral neuropathy

Recent evidence from animal models of diabetes and human diabetic subjects suggests that the reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic peripheral neuropathy (DPN). Of these proteins, nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin (NT-3) and NT-4/5 appear to be important for the development and maintenance of peripheral neurons, but others, including insulin-like growth factors (IGFs), may also be involved. Studies with NGF, NT-3, IGF-I and IGF-II both in vitro and in animal models of neuropathies (including DPN) suggest that these factors ameliorate nerve degeneration. Recombinant human NGF is the first neurotrophic factor to enter clinical trials for DPN and is currently being tested in two phase III studies.     

Insulin treatment enhances expression of IGF-I in sural nerves of diabetic patients

We studied the expression of insulin-like growth factor I (IGF-I) and its receptor in sural nerves from 8 diabetic patients divided into insulin-treated (IT) and non-insulin-treated (NIT) groups, compared with 5 patients with axonal neuropathies and 4 control patients (undergoing biopsies for diagnostic purposes). Insulin-like growth factor I mRNA levels did not differ in diabetic cases compared with control subjects. In sural nerves from IT patients and axonal neuropathies, IGF-I expression was higher than in NIT subjects and diagnostic controls. Changes in IGF-I receptor mRNA levels paralleled those of the ligand. Insulin-like growth factor I immunoreactivity was higher in nerves undergoing axonal degeneration and higher in IT than NIT diabetic patients and diagnostic controls. These findings suggest that insulin treatment increases IGF-I expression in diabetic nerves. Our data do not support the hypothesis of an absolute IGF-I deficiency in human diabetic neuropathy. A Schwann cell's incapacity to increase IGF-I expression after severe nerve damage, as happens in axonal neuropathies, may be a cofactor in the pathogenesis of diabetic neuropathy.     

Nerve growth factor gene therapy in Alzheimer disease

Nervous system growth factors potently stimulate cell function and prevent neuronal death. These broad effects on survival and function arise from direct downstream activation of antiapoptotic pathways, inhibition of proapoptotic pathways, and stimulation of functionally important cellular mechanisms including ERK/MAP kinase and CREB. Thus, as a class, growth factors offer the potential to treat neurodegenerative disorders for the first time by preventing neuronal degeneration rather than compensating for cell loss after it has occurred. Different growth factors affect distinct and specific populations of neurons: the first nervous system growth factor identified, nerve growth factor, potentially stimulates the survival and function of basal forebrain cholinergic neurons, suggesting that nerve growth factor could be a means for reducing the cholinergic component of cell degeneration in Alzheimer disease. This review will discuss the transition of growth factors from preclinical studies to human clinical trials in Alzheimer disease. The implementation of clinical testing of growth factor therapy for neurologic disease has been constrained by the dual need to achieve adequate concentrations of these proteins in specific brain regions containing degenerating neurons, and preventing growth factor spread to nontargeted regions to avoid adverse effects. Gene therapy is one of a limited number of potential methods for achieving these requirements.     

血管内皮生长因子与周围神经病变

简介VEGF及其受体的结构和功能,复习VEGF在糖尿病引起的外周神经病变以及其他类型神经病变的发生过程中所起的作用。研究显示转基因或其他干VEGF的措施,可能成为将来治疗一些神经病变的有效措施之一。     

Neuropathological and histochemical changes in a multiple mitochondrial DNA deletion disorder

The identification of cytochrome c oxidase (COX)-deficient/succinate dehydrogenase (SDH)- positive cells using sequential histochemistry has proved important in the identification of cells with high mitochondrial DNA (mtDNA) mutant load. We demonstrate large numbers of COX-deficient/SDH-positive neurons in a mosaic pattern throughout the CNS of a patient with a multiple mtDNA deletion disorder. This patient had prominent central and peripheral nervous system involvement with marked cerebellar ataxia, a parkinsonian extra-pyramidal movement disorder, external ophthalmoplegia, dysphagia, and a severe peripheral neuropathy. There was degeneration of myelin tracts in the cerebellum and dorsal spinal columns, diffuse astrocytosis, and selective neuronal degeneration particularly in the midbrain and cerebral microvacuolation. The proportional distribution of the COX-deficient neurons did not always correlate directly with the degree of neuropathological damage with regions of high neuronal loss having relatively low proportions of these cells. Other clinically affected CNS regions have high levels of COX-deficient neurons without significant cell loss. The role of these COX-deficient neurons in causing neuronal degeneration and clinical symptoms is discussed.     

Role of neurotrophic factors in enhancing linear axonal growth of ganglionic sensory neurons in vitro

Neurotrophins play a major role in the regulation of neuronal growth such as neurite sprouting or regeneration in response to nerve injuries. The role of nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor in maintaining the survival of peripheral neurons remains poorly understood. In regenerative medicine, different modalities have been investigated for the delivery of growth factors to the injured neurons, in search of a suitable system for clinical applications. This study was to investigate the influence of nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor on the growth of neurites using two in vitro models of dorsal root ganglia explants and dorsal root ganglia-derived primary cell dissociated cultures. Quantitative data showed that the total neurite length and tortuosity were differently influenced by trophic factors. Nerve growth factor and, indirectly, brain-derived neurotrophic factor stimulate the tortuous growth of sensory fibers and the formation of cell clusters. Neurotrophin-3, however, enhances neurite growth in terms of length and linearity allowing for a more organized and directed axonal elongation towards a peripheral target compared to the other growth factors. These findings could be of considerable importance for any clinical application of neurotrophic factors in peripheral nerve regeneration. Ethical approval was obtained from the Regione Piemonte Animal Ethics Committee ASLTO1(file # 864/2016-PR) on September 14, 2016.     

Peptide growth factors but not ganglioside protect against excitotoxicity in rat retinal neurons in vitro

Glutamate is the major excitatory neurotransmitter in the retina, but excessive stimulation of its receptors leads to widespread neuronal stress and death. Both growth factors and gangliosides display important influences on responses to neuronal injury and degeneration. In this study, we have investigated the potential protective effects of two well characterized growth factors, epidermal and basic fibroblast growth factor (EGF and bFGF respectively), and the monosialoganglioside GM1, on cultured rat retinal neurons submitted to toxic levels of excitatory amino acids. Application of 1 mM glutamic acid reduced global neuronal viability by 80% when compared to control untreated cultures, whereas treatment with the glutamic acid agonist kainic acid (1 mM) led to specific, large decreases (75% reduction) in amacrine cell numbers. 24 h pretreatment with either EGF or bFGF (500 pM each) prevented the majority of excitatory amino acid-induced neuronal death, whereas similar treatment with 10⁻⁵ M GM1 did not block neuronal degeneration. These findings demonstrate that EGF and bFGF act as neuroprotective agents against retinal excitotoxicity in vitro, whereas ganglioside GM1 is not effective in this particular paradigm.