Experimental strategies to promote axonal regeneration after traumatic central nervous system injury

A damage or pathological process that destroys the continuity of axons in the mature central nervous system (CNS) has devastating consequences and produces lasting functional deficits. One of the major challenges in this field is to stimulate the regrowth of severed axons and reconstruction of pathways. Recent progress in molecular and cell biology has resulted in an explosion of knowledge on factors in the adult CNS being nonsupportive or even actively inhibitory to axonal regrowth. The new findings have a strong impact on the development of new therapeutic concepts directed to stimulate axonal regeneration. They give rise to cautious optimism, showing that under some circumstances repair of a CNS lesion is possible. In this review the authors summarize the current knowledge on the factors and mechanisms involved in regeneration failure and provide an overview of the current therapeutic approaches that may enable effective CNS regeneration in the future.     

Identification of an 8-lipoxygenase pathway in nervous tissue of Aplysia californica

Arachidonic acid is converted to (8R)-hydroperoxyeicosa-5,9,11, 14-tetraenoic acid (8-HPETE) during incubations with homogenates of the central nervous system of the marine mollusc, Aplysia californica. 8-HPETE can be reduced to the corresponding hydroxy acid or be enzymatically converted to a newly identified metabolite, 8-ketoeicosa-5,9,11,14-tetraenoic acid (8-KETE). These metabolites were identified by high performance liquid chromatography, UV absorbance, and gas chromatography/mass spectrometry. Stereochemical analysis of the products demonstrate that the neuronal enzyme is an (8R)-lipoxygenase. Previously we have shown that the neurotransmitters, histamine and Phe-Met-Arg-Phe-amide, activate 12-lipoxygenase metabolism in isolated identified Aplysia neurons. We now show that acetylcholine activates the (8R)-lipoxygenase pathway within intact nerve cells. Thus, both (12S)- and (8R)-lipoxygenase co-exist in intact Aplysia nervous tissue but are differentially activated by several neurotransmitters. The precise physiological role of the 8-lipoxygenase products is currently under investigation, but by analogy to the well-described 12-lipoxygenase pathway, we suggest that (8R)-HPETE and 8-KETE may serve as second messengers in Aplysia cholinoceptive neurons.     

Serotonin immunoreactivity in the central nervous system of the marine molluscs Pleurobranchaea californica and Tritonia diomedea

The central nervous systems of the marine molluscs Pleurobranchaea californica (Opisthobranchia: Notaspidea) and Tritonia diomedea (Opisthobranchia: Nudibranchia) were examined for serotonin-immunoreactive (5-HT-IR) neurons and processes. Bilaterally paired clusters of 5-HT-IR neuron somata were distributed similarly in ganglia of the two species. In the cerebropleural ganglion complex, these were the metacerebral giant neurons (both species), a dorsal anterior cluster (Pleurobranchaea only), a dorsal medial cluster including identified neurons of the escape swimming network (both species), and a dorsal lateral cluster in the cerebropleural ganglion (Pleurobranchaea only). A ventral anterior cluster (both species) adjoined the metacerebral giant somata at the anterior ganglion edge. Pedal ganglia had the greatest number of 5-HT-IR somata, the majority located near the roots of the pedal commissure in both species. Most 5-HT-IR neurons were on the dorsal surface of the pedal ganglia in Pleurobranchaea and were ventral in Tritonia. Neither the buccal ganglion of both species nor the visceral ganglion of Pleurobranchaea had 5-HT-IR somata. Afew asymmetrical 5-HT-IR somata were found in cerebropleural and pedal ganglia in both species, always on the left side. The clustering of 5-HT-IR neurons, their diverse axon pathways, and the known physiologic properties of their identified members are consistent with a loosely organized arousal system of serotonergic neurons whose components can be generally or differentially active in expression of diverse behaviors.     

Functional effects of neural grafting in the mammalian central nervous system.

Grafts of fetal and nonfetal brain tissues have been successfully implanted into the mammalian central nervous system (CNS). The functional effects of neural grafting in the CNS of rodents and nonhuman primates in a variety of situations are reviewed. Research areas discussed include the effects of dopamine-rich grafts in animal models of Parkinson's disease and acetylcholine-rich grafts in animals with lesions of the cholinergic pathways to the neocortex and hippocampus. Graft effects also are examined in aged animals and genetic mutants. In addition, the effects of neural grafts on circadian rhythmicity, reproductive functions, and conditioned taste aversion are discussed. The beneficial functional effects of neural grafts and the possible mechanisms and implications for these effects are discussed, including the possibility that the CNS exhibits a regional biochemical specificity that influences the outcome of neural graft procedures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Astrocytic and neuronal factors affecting axon regeneration in the damaged central nervous system

Whether an axon will regenerate after it is cut depends on the balance between the intrinisic ability of the axon to regrow and the permissiveness of the environment surrounding it. The permissiveness of the environment is determined by the glial cells at the site of injury, and in the CNS both oligodendrocytes and astrocytes produce inhibitory molecules. Neurones differ greatly in the ability of their axons to regrow following axotomy. This intrinsic growth ability is greater in embryonic than adult neurones, varies from one neuronal type to another, depends on whether the axon is cut close to or far from the cell body, and can be increased by appropriate neurotrophic molecules.     

Ontogeny of serotonergic neurons in Aplysia californica

Although the functions of serotonin in adult Aplysia have been the focus of numerous investigations, our understanding of the roles played by this neurotransmitter during development is very incomplete. In the previous study (Marois and Carew [1997a] J. Comp. Neurol. 386:477-490), we showed that identified serotonergic cells are present very early during the ontogeny of Aplysia. In order to gain insight into the possible functions that these serotonergic cells may exert, we have used immuno-electron microscopy in this study to examine the projection patterns and target tissues of the serotonergic cells during the larval development of Aplysia. The results indicate that the larval serotonergic cells have numerous and precise connections to non-neuronal and neuronal target tissues: Serotonergic cells innervate the ciliated cells of the velum, numerous muscle systems, possibly visceral organs, and several cells in the central nervous system. Repeated observations of one serotonergic contact onto an undifferentiated neuron in the abdominal ganglion over a short developmental time span suggest that the serotonergic input may trigger axonogenesis in the postsynaptic cell. Apart from this possibility, we suggest that the innervation patterns of the larval serotonergic cells essentially fulfill the same primary function attributed to the adult serotonergic cells, that of modulating ongoing physiological and behavioral activity.     

Reeducation and spontaneous recovery of motor function in lesions of the nervous central system

A review is made of the current concepts on the several techniques (kinesitherapy programs) used with the purpose of recovering motor impairments caused by damage of the central nervous system. In this way data are gathered for the discussion and explanation of the intricate mechanisms involved in reeducation and recovery of the motor ability.     

Morphological changes in the central nervous system of animals depending on the dosage and time elapsed after exposure to low let radiation

Analytical review of the morphological investigations of cerebral cortex neurons of various animals shortly after exposure to X- and gamma-radiation was made. Considered were data of qualitative and quantitative analyses of dystrophic changes in neurons of the sensorimotor cortex of the large cerebral hemispheres of rats immediately and a long period since X-irradiation. Results of the quantitative analysis of structural disorders in the central nervous system neurons suggest radiation-produced damages early after exposure of animals to relatively low doses. Higher incidence of irreversible changes in neurons of the experimental animals, as compared with intact controls, was stimulated by the doses of no more than 0.25 to 1.0 Gy. The relative number of structural disorders in neurons and percentage of irreversibly impaired cells rose proportionally to the dose growth and further delay of the time of investigation. Possible mechanisms of delayed disorders that led to a massive building-up of the number of dystrophic neurons following 3 to 4 months post irradiation of rats are discussed.     

Tumors of the central nervous system

Neoplasia of the central nervous system (CNS) can be divided into two main categories: nonpituitary CNS neoplasia and pituitary adenomas. Nonpituitary CNS neoplasias are generally compressive in nature, although some are also invasive. The majority of reported CNS tumors are secondary with only a few originating from nervous tissue. Pituitary adenomas predominantly occur in the pars intermedia of the older horse. Clinical signs, diagnostic testing, and possible treatments are discussed.     

Remyelination of the central nervous system

The three typical stages in the clinical course of multiple sclerosis (relapse, persistent disability and progression) can be explained on the basis of inflammation, demyelination and failure of repair leading to axon degeneration and astrocytosis. Strategies are being evaluated for limiting the inflammatory process using immunological treatments and these may have unexpected dividends in promoting endogenous remyelination. Increasing knowledge on glial lineages and axon-glial interactions needed for stable myelination also offer the prospect for enhancing remyelination through growth factor therapy and cell implantation.     

Distribution of glial fibrillary acidic protein in central nervous system lesions of tuberous sclerosis

The distribution of glial fibrillary acidic protein (GFAP) in the central nervous system (CNS) lesions of tuberous sclerosis (TS) was examined using antiserum against GFAP and the peroxidase antiperoxidase method of Sternberger. In cortical tubers there were islands of gemistocytic astrocytes staining intensely for GFAP and occasional giant cells having some cytoplasmic staining. The majority of the cortical giant cells had no GFAP. The islands were separated by areas devoid of astrocytes with perikaryal staining. A faintly staining fibrous network was found between these islands. The majority of cells in the subependymal nodules stained. The retinal phakoma stained but not as intensely as the subependymal nodules. There was no staining whatsoever in the giant cell subependymal tumors. Absence of GFAP staining in the subependymal giant cell tumors makes their classification as astrocytomas less certain.     

Stem cells in the central nervous system

In the vertebrate central nervous system, multipotential cells have been identified in vitro and in vivo. Defined mitogens cause the proliferation of multipotential cells in vitro, the magnitude of which is sufficient to account for the number of cells in the brain. Factors that control the differentiation of fetal stem cells to neurons and glia have been defined in vitro, and multipotential cells with similar signaling logic can be cultured from the adult central nervous system. Transplanting cells to new sites emphasizes that neuroepithelial cells have the potential to integrate into many brain regions. These results focus attention on how information in external stimuli is translated into the number and types of differentiated cells in the brain. The development of therapies for the reconstruction of the diseased or injured brain will be guided by our understanding of the origin and stability of cell type in the central nervous system.     

Cytokine actions in the central nervous system

Cytokines and chemokines have been implicated in contributing to the initiation, propagation and regulation of immune and inflammatory responses. Also, these soluble mediators have important roles in contributing to a wide array of neurological diseases such as multiple sclerosis, AIDS Dementia Complex, stroke and Alzheimer's disease. Cytokines and chemokines are synthesized within the central nervous system by glial cells and neurons, and have modulatory functions on these same cells via interactions with specific cell-surface receptors. In this article, I will discuss the ability of glial cells and neurons to both respond to, and synthesize, a variety of cytokines. The emphasize will be on three select cytokines; interferon-gamma (IFN-gamma), a cytokine with predominantly proinflammatory effects; interleukin-6 (IL-6), a cytokine with both pro- and anti-inflammatory properties; and transforming growth factor-beta (TGF-beta), a cytokine with predominantly immunosuppressive actions. The significance of these cytokines to neurological diseases with an immunological component will be discussed.     

Glutamate receptors in the central nervous system

A lot of clinical processes following excessive stimulation of glutamate receptors seem to participate in pathophysiology of numerous acute and chronic neurological disorders. The whole of these reactions has been named as "glutamate cascade", because of the central role of glutamate in initiation and intensification of these processes. In this article, classification of different types of glutamate receptors and several hypotheses concerning mechanisms of glutamate neurotoxic activity are presented. A wide variety of neurological diseases, which etiologies are more or less connected with glutamate toxicity are discussed. At last, the future perspectives for treatment by drugs which action is thought to be mediated through glutamate receptors are presented.     

Cyclooxygenases and the central nervous system

Prostaglandins (PGs) were first described in the brain by Samuelsson over 30 years ago (Samuelsson, 1964). Since then a large number of studies have shown that PGs are formed in regions of the brain and spinal cord in response to a variety of stimuli. The recent identification of two forms of cyclooxygenase (COX; Kujubu et al., 1991; Xie et al., 1991; Smith and DeWitt, 1996), both of which are expressed in the brain, along with superior tools for mapping COX distribution, has spurred a resurgence of interest in the role of PGs in the central nervous system (CNS). In this review we will describe new data in this area, focusing on the distribution and potential role of the COX isoforms in brain function and disease.     

Aging and the central nervous system

This review of the literature on aging and the central nervous system attempts to cover the basic perameters investigated at both human and infrahuman levels for the better part of the last century. The results have indicated that there is a rather considerable lack of consistency in the data both within the frame of reference of a single species, and with regard to intraspecies comparisons. We have suggested that possible reasons for the contradictory findings would rest upon variability in techniques employed but, perhaps more importantly, on the failure of investigators in this area to standardize terminology. It is suggested that such a standardization might well be one of the more useful things to be accomplished in order to facilitate the interpretation of future work. The literature review first dealt with gross, i.e., macroscopic changes in brain morphology that could correlate with age, and then covered changes at the microscopic level. Finally, a brief review of the literature with regard to the biochemistry of aging was carried out. Implications of the data were noted where appropriate.     

Autoantibodies in central nervous system lupus

Central nervous system (CNS) involvement in patients with lupus remains both a diagnostic and a therapeutic challenge. The role of autoantibodies in the pathogenesis of CNS lupus and/or as markers for disease activity is reviewed. Doubt is cast on the value of measuring anti-neuronal antibodies. Those antibodies binding ribosomal-P protein antigens or certain phospholipids appear to have greater utility, although even in these cases there is no uniform agreement as to their precise role in CNS disease induction, or how well antibody levels reflect disease activity.     

Stem cells of the central nervous system

BACKGROUND: The aim of the present study was to analyze whether minor differences in recipient body surface area have any predictive value on renal allograft evolution. METHODS: For this study, we considered 236 pairs of recipients who received a kidney from the same donor at our center between March 1985 and December 1995. Pairs in whom at least one patient presented any of the following events were excluded: graft loss during the first year of follow-up, diabetes mellitus, noncompliance with treatment, chronic pyelonephritis, and recurrent or de novo glomerulonephritis. Recipients of each pair were classified as large or small according to their body surface area (BSA). The percentage difference of BSA in each pair was calculated, and two cohorts of pairs were defined: BSA difference < or = 10% (n=76 pairs) and BSA difference >10% (n=70 pairs). RESULTS: The large recipients of the cohort with a BSA difference >10% showed a higher incidence of posttransplant delayed graft function (22/70 vs. 12/70, P=0.075), hypertension at 1 year of follow-up (51/70 vs. 35/70, P=0.006), and a higher serum creatinine level at 1-year follow-up (173 vs. 142 micromol/L, P=0.003), whereas in the cohort with a BSA difference < or = 10%, posttransplant evolution in large and small recipients was not different. Multivariate analysis showed that recipient BSA was an independent predictor of delayed graft function, posttransplant hypertension, and serum creatinine at 1-year follow-up. CONCLUSIONS: Relatively small differences in recipient BSA influence renal allograft evolution. Consequently, our data support that recipient size should be taken into consideration for renal allograft allocation.