Search

A comprehensive understanding of the molecular pathways activated by traumatic neural injury is of major importance for the development of treatments for spinal cord injury (SCI). High-throughput gene expression profiling is a powerful approach to reveal genome-wide changes in gene expression during a specific biological process. Microarray analysis of injured nerves or neurons would ideally generate new hypotheses concerning the progression or deregulation of injury- and repair-related biological processes, such as neural scar formation and axon regeneration. These hypotheses should subsequently be tested experimentally and would eventually provide the molecular substrates for the development of novel therapeutics. Over the last decade, this approach has elucidated numerous extrinsic (mostly neural scar-associated) as well as neuron-intrinsic genes that are regulated following an injury. To date, the main challenge is to translate the observed injury-induced gene expression changes into a mechanistic framework to understand their functional implications. To achieve this, research on neural repair will have to adopt the conceptual advances and analytical tools provided by the functional genomics and systems biology revolution. Based on progress made in bioinformatics, high-throughput and high-content functional cellular screening, and in vivo gene transfer technology, we propose a multistep "roadmap" that provides an integrated strategy for molecular target discovery for repair of the injured spinal cord.

Publisher Summary This chapter presents an introduction to the seventeenth C.U. Ariens Kappers Lecture. The C.U. Ariens Kappers Award was created to honor the first director of the Netherlands Institute for Brain Research. Cornelius Ubbo Ariens Kappers was born in Groningen in 1877 and became the first director of the Netherlands (Central) Institute for Brain Research, a position he held until his death in 1946. The award is presented approximately once every two years to a leading and outstanding neuroscientist. With his excellent work, he turned the institute into an internationally renowned place and the three-volume book of which he wrote the English version together with Dr. G.C. Huber and Dr. E.C. Crosby, entitled “The Comparative Anatomy of the Nervous System of Vertebrates, including Man (1936),” became a classic and is still well cited. Dr. Clifford B. Saper was invited to deliver the seventeenth C.U. Ariens Kappers Lecture during the 24th International Summer School of Brain Research on September 1, 2005, for his outstanding achievements in deciphering the neuroanatomy of the mammalian hypothalamus and its intricate pathways involved in the control of behavior and physiology of the organism. Dr. Saper was born in Chicago and received his training in biochemistry and neurobiology at the University of Illinois in Urbana, Illinois and his medical training at Washington University School of Medicine in St. Louis, Missouri. In the course of his career, he has received several awards among which are the McKnight Scholar Award, Javits Neuroscience Investigator Award and the Carl Ludwig Award of the American Physiological Society.

This chapter reviews the steady advances that have been made in neuroregeneration research with the development of advanced gene and cell therapy to promote regeneration in animal models for spinal cord injury (SCI). It also includes a brief description of the pathophysiology of SCI and the predominantly used animal models. Spinal cord repair strategies comprise a multi-factorial approach addressing several issues, including the optimization of survival and function of the spared central nervous system neurons and the modulation of trophic and inhibitory influences to promote and guide axonal regrowth. Viral vector-mediated transfer of neurotrophic factor genes by direct vector injections is emerging as a novel and effective strategy to express neurotrophic proteins in the injured nervous system, including the spinal cord. Ex vivo transfer of neurotrophic factor genes is additionally explored a way to more efficiently bridge lesion cavities with cellular implants for axonal regeneration. Several viral vector systems, based on herpes simplex virus, adenovirus, adeno-associated virus, lentivirus and moloney leukemia virus have been employed. The genetic modification of fibroblasts, Schwann cells, olfactory ensheathing glia cells and stem cells, prior to implantation to the injured spinal cord has resulted in improved cellular nerve guides. The developed therapy includes a combination of growth-promoting molecules either delivered via genetically modified cells or by direct gene transfer as discussed in this review and the neutralization of outgrowth inhibitory factors present in central nervous system myelin and in the neural scar.

Injuries to the adult mammalian spinal cord often lead to severe damage to both ascending (sensory) pathways and descending (motor) nerve pathways without the perspective of complete functional recovery. Future spinal cord repair strategies should comprise a multi-factorial approach addressing several issues, including optimalization of survival and function of spared central nervous system neurons in partial lesions and the modulation of trophic and inhibitory influences to promote and guide axonal regrowth. Neurotrophins have emerged as promising molecules to augment neuroprotection and neuronal regeneration. Although intracerebroventricular, intrathecal and local protein delivery of neurotrophins to the injured spinal cord has resulted in enhanced survival and regeneration of injured neurons, there are a number of drawbacks to these methods. Viral vector-mediated transfer of neurotrophin genes to the injured spinal cord is emerging as a novel and effective strategy to express neurotrophins in the injured nervous system. Ex vivo transfer of neurotrophic factor genes is explored as a way to bridge lesions cavities for axonal regeneration. Several viral vector systems, based on herpes simplex virus, adenovirus, adeno-associated virus, lentivirus, and moloney leukaemia virus, have been employed. The genetic modification of fibroblasts, Schwann cells, olfactory ensheathing glia cells, and stem cells, prior to implantation to the injured spinal cord has resulted in improved cellular nerve guides. So far, neurotrophic factor gene transfer to the injured spinal cord has led to results comparable to those obtained with direct protein delivery, but has a number of advantages. The steady advances that have been made in combining new viral vector systems with a range of promising cellular platforms for ex vivo gene transfer (e.g., primary embryonic neurons, Schwann cells, olfactory ensheating glia cells and neural stem cells) holds promising perspectives for the development of new neurotrophic factor-based therapies to repair the injured nervous system.

Publisher Summary The vigorous regrowth of injured axons in the peripheral nervous system (PNS) contrasts with the observed failure of axonal regeneration in the mammalian central nervous system (CNS). This dichotomy is due to a different microenvironment at the site of the lesion and a differential intrinsic capacity of CNS and PNS neurons to activate a program of gene expression that supports regeneration. This chapter focuses on recent observations that suggest a possible role for semaphorin III and its recently identified receptor neuropilin- 1 in axonal regeneration and scar formation. First, a general introduction on inhibitory mechanisms that appear to prevent successful axonal regeneration in the CNS is provided. Subsequently, recent evidence for a role of semaphorin/neuropilin signaling in axonal regeneration in the PNS and CNS is reviewed. The recently observed downregulation of semaphorin III in motor neurons following a peripheral nerve crush and the induction of semaphorin III in CNS scar tissue argues that the regulation of the expression of some members of the semaphorin gene family may contribute significantly to the failure or success of the neuroregeneration process.

Publisher Summary Alzheimer's disease (AD) is the most common cause of dementia in elderly people and constitutes the fourth most common cause of death in Western society. One of the potential therapeutic strategies for AD is the use of neurotrophins. It has been proposed that the degenerative changes in neurodegenerative disorders, including AD are the result of lack of trophic support. AD is characterized by the presence of a large number of plaques, neurofibrillary tangles, and diminished neuronal activity. The rationale for the involvement of neurotrophins in the neurodegenerative process of AD is based on the following observations given in this chapter: (1) normally abundant expression of nerve growth factor (NGF) mRNA is found in the cerebral cortex and hippocampus, (2) the highest levels of low affinity neurotrophin receptors are present in the basal forebrain area (3) there is a considerable degree of colocalization between choline acetyltransferase (ChAT) and neurotrophin receptors in the basal forebrain of rat and human (4) the ability of intraventricular-administrated NGF to increases ChAT activity in the basal forebrain of neonatal rats (5) protective effects of NGF on fiber sprouting and improved transmitter-dependent functions of basal forebrain cholinergic neurons in adult rats following lesions, (6) the ability of basal forebrain neurons to retrogradely transport NGF, and (7) the ability of exogenous NGF to reverse cholinergic atrophy and memory impairment in old rats.

Publisher Summary This chapter develops experimental gene therapy strategies, based on gene transfer with defective viral vectors, to promote neuroregeneration. The main focus is the generation of herpes simplex and adenovirus vectors for this growth-associated protein together with their application in vitro and in vivo—that is, viral vector-mediated gene transfer of B-50/GAP43, a neural growth-associated protein implicated in the formation of nerve fibers. Direct viral vector-mediated transduction of genes to neural cells following injury provides new functions to these cells. Therefore, this approach aims at the direct delivery and expression of putative therapeutic genes to injured neurons and to glial cells in an injured nerve tract. . The mammalian nervous system consists of cellular networks formed by neurons and their projections and glial cells. The integrity of this complex cellular structure is essential for the proper execution of all body functions. Injury inflicted upon central nervous system (CNS) neurons poses major problems to patients and their neurologists. Two crucial aspects of the repair process are considered as important future targets for genetic intervention. First, the (over)expression of neuron survival promoting and axonal guidance molecules in post-traumatic neurons could result in neuron rescue or could promote regenerative sprouting and nerve fiber fasciculation. Second, gene-transfer experiments are devised to disrupt the cellular and molecular events that result in the formation of neural scar tissue. Successful genetic intervention in neurogeneration can probably only be achieved by simultaneous attempts to stimulate neuron survival and sprouting following trauma and by reversing and/or counteracting the nonpermissive environment in the area of the lesion.