Induction of metallothionein in astrocytes and microglia in the spinal cord from the myelin-deficient jimpy mouse

Jimpy is a shortened life-span murine mutant whose genetic disorder results in severe pathological alterations in the CNS, including hypomyelination, oligodendrocyte death and strong astroglial and microglial reaction. The knowledge of metallothionein (MT) regulation in the CNS and especially of MT presence in specific glial cell types under pathological conditions is scarce. In the present study, immunocytochemical detection of MT-I + II has been performed in spinal cord sections from 10-12- and 20-22-day-old jimpy and normal animals. The identification of MT-positive glial cells was achieved through double labeling combining MT immunocytochemistry and selective markers for oligodendrocytes, astrocytes and microglia. MT was found in glial cells and was present in the spinal cord of jimpy and normal mice at both ages, but there were remarkable differences in MT expression and in the nature of MT-positive glial cells depending on the type of mouse. The number of MT-positive cells was higher in jimpy than in normal spinal cords. This was apparent in all spinal cord areas, although it was more pronounced in white than in the gray matter and at 20-22 days than at 10-12 days. The mean number of MT-positive glia in the jimpy white matter was 1.9-fold (10-12 days) and 2.4-fold (20-22 days) higher than in the normal one. Astrocytes were the only parenchymal glial cells that were positively identified as MT-producing cells in normal animals. Interestingly, MT in the jimpy spinal cord was localized not only in astrocytes but also in microglial cells. The occurrence of MT induction in relation to reactive astrocytes and microglia, and its role in neuropathological conditions is discussed.     

An approach to genetic transformation in the Xiphophorine fish

The paper describes the clinical and morphological features of a congenital neurological disease affecting two in-bred litter-mate kittens. The principal neurological features were ataxia and dysmetria. In one of the kittens light microscopy revealed widespread vacuolation of white and grey matter of the brain and spinal cord. Electron microscopy revealved intra-myelinic vacuolation and some expansion of the extracellular space. Neuronal, axonal and glial changes were not seen, nor was there evidence of myelin breakdown. The entity is compared with congenital brain oedema of calves and spongy degeneration of the CNS in man.     

Alterations in temporal/spatial distribution of GFAP- and vimentin-positive astrocytes after spinal cord contusion with the New York University spinal cord injury device

Astrocytes become reactive as a result of various types of lesions and upregulate 2 intermediate filaments, glial fibrillary acidic protein (GFAP), and the developmentally regulated protein vimentin. Young female Sprague-Dawley rats were subjected to a spinal cord contusion at segment T10 using the New York University injury device. Animals were killed at 1, 2, 7, 14, and 30 days postinjury. Horizontal spinal cord sections spanning segments T7-T13 were assessed with antibodies to both intermediate filament proteins. The number of gray matter GFAP-positive astrocytes increased by 2 days postinjury, with segments adjacent (proximal) to the injury site showing greater responses than areas several segments away (distal). By 30 days following injury, astroglial cell numbers returned to normal levels. Vimentin-positive astrocytes also showed a graded proximal/distal response by 2 days following injury. Proximal regions remained significantly higher at 30 days following injury than control animals. Rostral/caudal changes were also evident, with regions caudal to the injury showing significantly higher numbers of vimentin positive astrocytes than those rostral, indicating that gray matter areas caudal to spinal cord injury may undergo more stress following spinal cord injury.     

The relationship between serum gamma-glutamyl transpeptidase levels and hypertension: common in drinkers and nondrinkers

Lesions in CNS white matter involving loss of glial cells with concurrent destruction of the glia limitans lead to widespread remyelination of CNS axons by Schwann cells. Previous studies have demonstrated that this situation can be changed by transplanting cultured CNS glial cells into lesions early on in the repair process. In this study we have transplanted cultured astrocytes into the sub-arachnoid space above such a lesion in order to (1) influence the normal repair process by transplant-assisted reconstruction of the glia limitans, and (2) explore the potential of a minimally invasive route for introducing cells to white matter lesions. In some cases, it proved possible to influence normal repair by transplanting cells via the sub-arachnoid route, although the results were inconsistent. However, the experiment permitted observations to be made on the migration of transplanted astrocytes across the surface of and within the spinal cord.     

Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain

The developmental fates of subventricular zone (SVZ) cells of the postnatal rat forebrain were determined by retroviral-mediated gene transfer and immunolabeling for glial antigens. A beta-galactosidase-containing retrovirus injected stereotactically into the SVZ infected small, immature cells. By 28 days post-injection labeled cells had appeared in both gray and white matter of the ipsilateral hemisphere. White matter contained labeled oligodendrocytes, but few astrocytes, while neocortex and striatum contained both glial types, often appearing in tightly knit clusters. An analysis after simultaneously injecting alkaline phosphatase- and beta-galactosidase-containing retroviruses showed that cells in each cortical cluster were related. Most clusters contained a single cell type, but approximately 15% contained both astrocytes and oligodendrocytes. These observations strongly suggest that a single SVZ cell can differentiate into both glial types.     

Axonal and nonneuronal cell responses to spinal cord injury in mice lacking glial fibrillary acidic protein

We have examined the regeneration of corticospinal tract fibers and expression of various extracellular matrix (ECM) molecules and intermediate filaments [vimentin and glial fibrillary acidic protein (GFAP)] after dorsal hemisection of the spinal cord of adult GFAP-null and wild-type littermate control mice. The expression of these molecules was also examined in the uninjured spinal cord. There was no increase in axon sprouting or long distance regeneration in GFAP-/- mice compared to the wild type. In the uninjured spinal cord (i) GFAP was expressed in the wild type but not the mutant mice, while vimentin was expressed in astrocytes in the white matter of both types of mice; (ii) laminin and fibronectin immunoreactivity was localized to blood vessels and meninges; (iii) tenascin and chondroitin sulfate proteoglycan (CSPG) labeling was detected in astrocytes and the nodes of Ranvier in the white matter; and (iv) in addition, CSPG labeling which was generally less intense in the gray matter of mutant mice. Ten days after hemisection there was a large increase in vimentin+ cells at the lesion site in both groups of mice. These include astrocytes as well as meningeal cells that migrate into the wound. The center of these lesions was filled by laminin+/fibronectin+ cells. Discrete strands of tenascin-like immunoreactivity were seen in the core of the lesion and lining its walls. Marked increases in CSPG labeling was observed in the CNS parenchyma on either side of the lesion. These results indicate that the absence of GFAP in reactive astrocytes does not alter axonal sprouting or regeneration. In addition, except for CSPG, the expression of various ECM molecules appears unaltered in GFAP-/- mice.     

The relation between rhinitis and allergic asthma. The action of antihistaminics on bronchial hyperreactivity

The intermediate filament nestin is highly expressed in multipotential stem cells of the developing central nervous system (CNS). During neuro- and gliogenesis, nestin is replaced by cell type-specific intermediate filaments, e.g. neurofilaments and glial fibrillary acidic protein (GFAP). In this study, we demonstrate that nestin expression is re-induced in reactive astrocytes in the lesioned adult brain. Following ischaemic and mechanical lesioning, a strong and sustained expression of nestin was noted in GFAP-positive cells surrounding the lesion site. Lesion experiments in transgenic mice carrying the lacZ gene under control of regulatory sequences from the nestin gene suggested that the upregulation of nestin in reactive astrocytes is mediated via the same sequences that control nestin expression during CNS development. These observations and recent data on the co-expression of glial and neuronal marker antigens in reactive astrocytes point to a close relationship between proliferating astrocytes and neuroepithelial precursor cells.     

Late-onset chronic inflammatory encephalopathy in immune-competent and severe combined immune-deficient (SCID) mice with astrocyte-targeted expression of tumor necrosis factor

To examine the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of degenerative disorders of the central nervous system (CNS), transgenic mice were developed in which expression of murine TNF-alpha was targeted to astrocytes using a glial fibrillary acidic protein (GFAP)-TNF-alpha fusion gene. In two independent GFAP-TNFalpha transgenic lines (termed GT-8 or GT-2) adult (>4 months of age) animals developed a progressive ataxia (GT-8) or total paralysis affecting the lower body (GT-2). Symptomatic mice had prominent meningoencephalitis (GT-8) or encephalomyelitis (GT-2) in which large numbers of B cells and CD4+ and CD8+ T cells accumulated at predominantly perivascular sites. The majority of these lymphocytes displayed a memory cell phenotype (CD44high, CD62Llow, CD25-) and expressed an early activation marker (CD69). Parenchymal lesions contained mostly CD45+ high, MHC class II+, and Mac-1+ cells of the macrophage microglial lineage with lower numbers of neutrophils and few CD4+ and CD8+ T cells. Cerebral expression of the cellular adhesion molecules ICAM-1, VCAM-1, and MAdCAM as well as a number of alpha- and beta-chemokines was induced or upregulated and preceded the development of inflammation, suggesting an important signaling role for these molecules in the CNS leukocyte migration. Degenerative changes in the CNS of the GFAP-TNFalpha mice paralleled the development of the inflammatory lesions and included primary and secondary demyelination and neurodegeneration. Disease exacerbation with more extensive inflammatory lesions that contained activated cells of the macrophage/microglial lineage occurred in GFAP-TNFalpha mice with severe combined immune deficiency. Thus, persistent astrocyte expression of murine TNF-alpha in the CNS induces a late-onset chronic inflammatory encephalopathy in which macrophage/microglial cells but not lymphocytes play a central role in mediating injury.     

Role of glial filaments in cells and tumors of glial origin: a review

In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). Glial fibrillary acidic protein is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.     

Co-expression of APP with cNOS but not iNOS after cortical injury in rat

Alterations in the expression of both the beta-amyloid precursor protein (APP) and nitric oxide synthase (NOS) might be involved in neurodegenerative conditions and/or in the neuronal response to injury. We have investigated the relationship between the increased expression of beta-amyloid precursor protein (APP) and the reactive changes in the expression of isoforms of nitric oxide synthase (NOS) in neurons and glial cells after small electrolytic lesions placed to the cerebral cortex. An increase in the expression of APP in both neurons and glial cells was detected 4 days post-operation. The inducible NOS (iNOS) was observed in macrophages or glial cells surrounding the lesion site. No major changes in constitutive NOS (cNOS) were found. APP immunoreactivity was not co-localized with either iNOS or cNOS at this survival time. At longer survival times (8 and 12 days post-lesion), a reactive increase in the expression of cNOS in cortical pyramidal neurons was seen in addition to the elevated expression of iNOS in astrocytes. The reactive expression of cNOS was confined to a subset of neurons also showing a high expression of APP. The present results suggest a relationship between reactive changes in the expression of APP and cNOS during the neuronal response to injury.     

Human herpesvirus-6 (HHV-6)-associated necrotizing encephalitis in Griscelli's syndrome

We report a male caucasian German pediatric patient of no Arab or Mediterranean ancestry with virus associated CNS lesions in Griscelli's syndrome (GS; McKusick No. 214450). The boy presented with recurrent infections, and meningitis with subsequent progressive signs of increased intracranial pressure leading to death at 32 weeks of age. At autopsy, various sites of the CNS revealed necroses in gray and white matter. CNS histology revealed numerous and massive predominantly perivascular CD8 positive lymphohistiocytic infiltrates. These findings were associated strictly with the presence of human herpesvirus-6 (HHV-6) genome or the HHV-6 specific late antigen H-AR 3, found in neurons, oligodendrocytes, and astrocytes. The search for HHV-6 replication dependent antigen, HHV-7 DNA, CMV, adenovirus, Coxsackie B1, B2, and B4-antigens, and mycobacteria was not successful. Detection of viruses was attempted using immunohistochemistry, in situ hybridization or nested polymerase chain reaction, respectively. Lymphocyte typing was carried out immunohistochemically. In GS, virus induced CNS damage does not seem to require necessarily active virus replication. It may also appear as a consequence of an immune reaction triggered by antigen expression.     

The use of transplanted glial cells to reconstruct glial environments in the CNS

Transplantation studies have demonstrated that glia-depleted areas of the CNS can be reconstituted by the introduction of cultured cells. Thus, the influx of Schwann cells into glia-free areas of demyelination in the spinal cord can be prevented by the combined introduction of astrocytes and cells of the O-2A lineage. Although Schwann cell invasion of areas of demyelination is associated with destruction of astrocytes, the transplantation of rat tissue culture astrocytes ("type-1") alone cannot suppress this invasion, indicating a role for cells of the O-2A lineage in reconstruction of glial environments. By transplanting different glial cell preparations and manipulating lesions so as to prevent meningeal cell and Schwann cell proliferation it is possible to demonstrate that the behaviour of tissue culture astrocytes ("type-1") and astrocytes derived from O-2A progenitor cells ("type-2") is different. In the presence of meningeal cells, tissue culture astrocytes clump together to form cords of cells. In contrast, type-2 astrocytes spread throughout glia-free areas in a manner unaffected by the presence of meningeal cells or Schwann cells. Thus, progenitor-derived astrocytes show a greater ability to fill glia-free areas than tissue culture astrocytes. Similarly, when introduced into infarcted white matter in the spinal cord, progenitor-derived astrocytes fill the malacic area more effectively than tissue culture astrocytes, although axons do not regenerate into the reconstituted area.     

Increased immunoreactivities for the basic fibroblast growth factor and its receptor in astrocytes at the site of cerebral lesions and oedematous change in SHR

1. To obtain information about changes of basic fibroblast growth factor (bFGF) in the brain in chronic hypertension, we immunohistochemically studied the distribution and level of bFGF and its receptor in the brain of stroke-prone spontaneously hypertensive rats (SHRSP). 2. In the control normotensive rats, immunoreactivity for bFGF was demonstrated in nerve cells, while there was almost no reactivity in astrocytes. 3. In SHRSP, there was a marked immunoreactivity in the densely accumulated reactive cells, particularly astrocytes, in and around cerebral cortical lesions. Slightly increased reaction for bFGF was found in the nerve cells around lesions. Astrocytes in the subcortical white matter on both ipsi- and contralateral sides of the cortical lesion also showed immunoreactivity for bFGF. The location of increased bFGF expression in SHRSP corresponded very well with the site of extravasated plasma fluid demonstrated by anti-fibrinogen antibody. Electron microscopically, bFGF was shown in astrocytes along the rough endoplasmic reticulum suggesting the growth factor to be produced in the cells and not to be taken up from the surroundings. Expression of FGF-receptor was also demonstrated in reactive astrocytes in the oedematous cortical portion around lesion and in the oedematous subcortical white matter. 4. These findings indicate the possibility that oedema and the simultaneously generated free radicals or some extravasated plasma components express bFGF in astrocytes and probably in nerve cells as well as FGF-receptor in astrocytes, and that the thus expressed bFGF and its receptor play some role in the sequence of developmental events of hypertensive cerebral lesions.     

Development and differentiation of glial precursor cells in the rat cerebellum

The development and differentiation of bipotential glial precursor cells has been studied extensively in tissue culture, but little is known about the distribution and fate of these cells within intact animals. To analyze the development of glial progenitor cells in the developing rat cerebellum, we utilized immunofluorescent, immunocytochemical, and autoradiographic techniques. Glial progenitor cells were identified with antibodies against the NG2 chondroitin-sulfate proteoglycan, a cell-surface antigen of 02A progenitor cells in vitro, and the distribution of this marker antigen was compared to that of marker antigens that identify immature astrocytes, mature astrocytes, oligodendrocyte precursors, and mature oligodendrocytes. Cells expressing the NG2 antigen appeared in the cerebellum during the last 3-4 days of embryonic life. Over the first 10 days of postnatal life, the NG2-labeled cells incorporated 3H-thymidine into their nuclei and their total number increased. At all ages examined, the NG2-labeled cells did not contain either vimentin-like or glial fibrillary acidic protein (GFAP)-like immunoreactivity, suggesting that they do not develop along an astrocytic pathway. NG2-labeled cells of embryonic animals expressed GD3 ganglioside antigens, a property of oligodendrocyte precursors, whereas NG2-positive cells of postnatal animals did not express GD3 immunoreactivity. Nevertheless, the NG2-labeled cells of the nascent white matter expressed oligodendrocyte-specific marker antigens. Cells lying outside of the white matter continued to express the NG2 antigen. In adult animals, the NG2-labeled cells incorporated 3H-thymidine. Glial cells isolated from adult animals and grown in tissue culture express the NG2 antigen and display the phenotypic plasticity characteristic of 02A progenitor cells. These findings demonstrate that a population of glial progenitor cells is extensive within both young and adult animals.     

Case report of unusual leukoencephalopathy preceding primary CNS lymphoma

A previously healthy 35 year old woman presented with bilateral uveitis associated with multiple, evolving, non-enhancing white matter lesions consistent with a progressive leukoencephalopathy such as multiple sclerosis. Thirty months after her initial presentation, she was diagnosed with primary CNS lymphoma and died 14 months later. The unusual clinical course preceding the diagnosis suggests that a demyelinating disease may have preceded, and possibly heralded, the development of primary CNS lymphoma. Cases of "sentinel lesions" heralding the diagnosis of primary CNS lymphoma have been reported, and this case further corroborates such instances and raises further issues regarding possible neoplastic transformation occurring in inflammatory diseases such as multiple sclerosis.     

Regeneration of adult axons in white matter tracts of the central nervous system

It is widely accepted that the adult mammalian central nervous system (CNS) is unable to regenerate axons. In addition to physical or molecular barriers presented by glial scarring at the lesion site, it has been suggested that the normal myelinated CNS environment contains potent growth inhibitors or lacks growth-promoting molecules. Here we investigate whether adult CNS white matter can support long-distance regeneration of adult axons in the absence of glial scarring, by using a microtransplantation technique that minimizes scarring to inject minute volumes of dissociated adult rat dorsal root ganglia directly into adult rat CNS pathways. This atraumatic injection procedure allowed considerable numbers of regenerating adult axons immediate access to the host glial terrain, where we found that they rapidly extended for long distances in white matter, eventually invading grey matter. Abortive regeneration correlated precisely with increased levels of proteoglycans within the extracellular matrix at the transplant interface, whereas successfully regenerating transplants were associated with minimal upregulation of these molecules. Our results demonstrate, to our knowledge for the first time, that reactive glial extracellular matrix at the lesion site is directly associated with failure of axon regrowth in vivo, and that adult myelinated white matter tracts beyond the glial scar can be highly permissive for regeneration.     

Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants

The lack of axonal regeneration in the injured adult mammalian spinal cord leads to permanent functional impairment. To induce axonal regeneration in the transected adult rat spinal cord, we have used the axonal growth-promoting properties of adult olfactory bulb ensheathing glia (EG). Schwann cell (SC)-filled guidance channels were grafted to bridge both cord stumps, and suspensions of pure (98%) Hoechst-labeled EG were stereotaxically injected into the midline of both stumps, 1 mm from the edges of the channel. In EG-transplanted animals, numerous neurofilament-, GAP-43-, anti-calcitonin gene-related peptide (CGRP)-, and serotonin-immunoreactive fibers traversed the glial scars formed at both cord-graft interfaces. Supraspinal serotonergic axons crossed the transection gap through connective tissue bridges formed on the exterior of the channels, avoiding the channel interior. Strikingly, after crossing the distal glial scar, these fibers elongated in white and periaqueductal gray matter, reaching the farthest distance analyzed (1.5 cm). Tracer-labeled axons present in SC grafts were found to extend across the distal interface and up to 800 microm beyond in the distal cord. Long-distance regeneration (at least 2.5 cm) of injured ascending propriospinal axons was observed in the rostral spinal cord. Transplanted EG migrated longitudinally and laterally from the injection sites, reaching the farthest distance analyzed (1.5 cm). They moved through white matter tracts, gray matter, and glial scars, overcoming the inhibitory nature of the CNS environment, and invaded SC and connective tissue bridges and the dorsal and ventral roots adjacent to the transection site. Transplanted EG and regenerating axons were found in the same locations. Because EG seem to provide injured spinal axons with appropriate factors for long-distance elongation, these cells offer new possibilities for treatment of CNS conditions that require axonal regeneration.     

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.     

Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study

Activation of glial cells and white matter changes (rarefaction of the white matter) induced in the rat brain by permanent bilateral occlusion of the common carotid arteries were immunohistochemically investigated up to 90 days. One day after ligation of the arteries, expression of the major histocompatibility complex (MHC) class I antigen in microglia increased in the white matter including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. After 3 days of occlusion, MHC class I antigen was still elevated and in addition MHC class II antigen and leukocyte common antigen were up-regulated in the microglia in these same regions. Astroglia, labeled with glial fibrillary acidic protein, increased in number in these regions after 7 days of occlusion. A few lymphocytes, labeled with CD4 or CD8 antibodies, were scattered in the neural parenchyma 1 h after occlusion. Activation of glial cells and infiltration of lymphocytes persisted after 90 days of occlusion in the white matter and the retinofugal pathway. However, cellular activation and infiltration in microinfarcts of the gray matter was less extensive and was substantially diminished 30 days after occlusion. The white matter changes were most intense in the optic nerve and optic tract, moderate in the medial part of the corpus callosum, internal capsule and anterior commissure, and slight in the fiber bundles of the caudoputamen. These results indicated that chronic cerebral hypoperfusion induced glial activation preferentially in the white matter. This activation seemed to be an early indicator of the subsequent changes in the white matter.     

Deprenyl induces GFAP immunoreactivity in the intact and injured dopaminergic nigrostriatal system but fails to counteract axotomy-induced degenerative changes

There is increasing evidence of a trophic-like mechanism for some effects ascribed to deprenyl therapy in the central nervous system. For that, we studied the effect of chronic treatment with deprenyl in an animal model of Parkinson's disease induced by unilateral knife transection of the medial forebrain bundle (MFB) in adult rats. The experimental conditions included a 3-week pretreatment with deprenyl before stereotaxic transection of the MFB. Following surgery, deprenyl treatment was maintained for 3 weeks. Neurochemical and immunohistochemical procedures were used to study the dopaminergic system and reactive astrocytes in the nigrostriatal system. Deprenyl treatment failed to counteract the axotomy-induced degenerative changes of the nigrostriatal dopaminergic system. However, it was effective in increasing the density of reactive astrocytes in terms of glial fibrillary acidic protein (GFAP) immunoreactivity in the intact contralateral substantia nigra and also in further enhancing the axotomy-induced increase of GFAP immunolabeled astrocytes in the lesioned substantia nigra. This deprenyl-induced effect on GFAP immunoreactivity was confined to substantia nigra without effect in striatum. In addition, we found a medial to lateral gradient decrease in the distribution pattern of GFAP immunolabeled astrocytes. Axotomy increased the number of reactive astrocytes in either striatal area examined, but yet the preferential distribution pattern of reactive astrocytes in striatum was still evident.