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V H Perry

Publications and source records attributed to V H Perry.

At least 91 records · Page 5Linked to original sources
PubMed1997

Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke.

Multiple sclerosis (MS) and stroke pathology are characterized blood-brain barrier breakdown, leucocyte emigration, and tissue destruction. Each process is thought to involve the matrix metalloproteinases (MMP), but little is known of their expression. We undertook to investigate whether MMP expression is dependent on the nature of the CNS lesion and whether expression would coincide with the histopathology. MS or cerebral-infarct tissue was examined for the presence of gelatinase-A, gelatinase-B, matrilysin and stromelysin-1. Gelatinases A and B and matrilysin expression was found to be up-regulated in microglia/macrophages within acute MS lesions. In active-chronic MS lesions, matrilysin and gelatinase-A expression was pronounced in the active borders. In chronic MS lesions, the expression of matrilysin was confined to macrophages within perivascular cuffs. The pattern of MMP expression in infarct lesions differed considerably. Gelatinase-B was strongly expressed by neutrophils in tissue from patients up to 1 week after an infarct, whereas gelatinase-A and matrilysin staining was much less marked. From 1 week to 5 years, neutrophils were absent and the large number of macrophages present were expressing matrilysin and gelatinase A. Only a low level of gelatinase-A and matrilysin expression was observed in normal brain controls. Thus, MMPs are expressed in inflammatory lesions in the CNS, but their individual expression is dependent on the nature and chronicity of the lesion. However, the general pattern of expression, in perivascular cuffs and in active lesions, supports a role for these enzymes as mediators of blood-brain barrier breakdown and tissue destruction, both in MS and in cerebral ischaemia.

Acute Disease↗
PubMed1996

Distribution of M retinal ganglion cells in diurnal and nocturnal New World monkeys.

The topography of M ganglion cell distribution was studied in the retinae of two New World monkey species, the diurnal capuchin monkey Cebus apella and the nocturnal owl monkey Aotus azarae. Retinal whole mounts were stained by the neurofibrillar method of Gros-Schultze. As occurs with other diurnal primates, the Cebus M-ganglion cell density peaks in the foveal slope and declines towards the periphery. In the Aotus retina, the M ganglion cell density peaks in the area centralis and declines toward the periphery. In both species the cell density in the temporal, dorsal, and ventral meridians are similar for equivalent eccentricities. The cell density in the nasal meridian is higher than in the other meridians. The naso-temporal density ratio ranges between 1.2 and 4.3 in the Cebus and 1.6 and 2.2 in the Aotus. The total number of M-ganglion cells was 140,300 and 74,000 in the Cebus and Aotus retinae, respectively, corresponding to about 10% and 15.4% of the total retinal ganglion cell population in these species. The results indicate that M ganglion cells are similarly organized in both diurnal and nocturnal simians, but may be proportionally more important for the nocturnal species.

Animals↗
PubMed1996

Factors affecting the survival of cat retinal ganglion cells after optic nerve injury.

After partial transection of one optic nerve in adult cats the majority of beta retinal ganglion cells degenerate and die 1 week after axotomy, whilst other cell classes degenerate slowly and survive for a long period after the lesion. We have investigated the effects of intravitreal and intraperitoneal injections of MK-801, a NMDA-glutamate receptor antagonist, on the early degeneration of retinal ganglion cells after partial optic nerve section. Control animals received saline intravitreal injections. Retinal flat mounts were retrogradely labelled with horseradish peroxidase and counterstained with Cresyl Violet. We evaluated the ganglion cell loss in the three experimental groups 1 week after lesion and compared them with normal uninjured controls and injured untreated retinae. In untreated retinae 49% of ganglion cells die 1 week after the lesion. Systemic MK-801 or saline prolonged survival of 41% of retinal ganglion cells that would die without treatment. Intravitreal MK-801 or saline prolonged survival of 71% of retinal ganglion cells that would die without treatment, but the results of saline administration had a larger range of variability. In untreated retinae many pyknotic cells were observed. They decreased in number after systemic MK-801 treatment and in some retinae treated with intravitreal injections of saline solution. There were no pyknotic cells after local, intravitreal MK-801 treatment. These results support the hypothesis that NMDA-receptor mediated neurotoxicity plays an important role in the early retinal ganglion cell death after retrobulbar axotomy. They also support the existence of an endogenous source of neurotrophins whose release is triggered by eyeball injury. We conclude that the early death of beta retinal ganglion cells after axotomy occurs by a mechanism that can be controlled by neurotrophins and antagonists to NMDA-glutamate receptors.

Animals↗
PubMed1996

Delayed-type hypersensitivity lesions in the central nervous system are prevented by inhibitors of matrix metalloproteinases.

We have studied the effect of an inhibitor of matrix metalloproleinases, BB-1101, on a delayed-type hypersensitivity (DTH) response in the CNS. We used a recently described model in which heat-killed bacillus Calmette-Guérin (BCG) sequestered behind the blood-brain barrier (BBB) is targeted by a T-cell mediated response after subcutaneous injection of BCG (Matyszak and Perry, 1995). The DTH lesions are characterised by breakdown of the BBB, macrophage and lymphocyte infiltration and tissue damage including myelin loss. Treatment with BB-1101, which is not only a potent inhibitor of matrix metalloproteinases but also strongly inhibits TNF-alpha release, dramatically attenuated the CNS lesions. Breakdown of the BBB and the recruitment of T-cells into the site of the lesion were significantly reduced. There were many fewer inflammatory macrophages in DTH lesions than in comparable lesions from untreated animals. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals treated with dexamethasone was also reduced, but to a lesser degree. No significant effect was seen after administration of pentoxifylline, a phosphodiesterase inhibitor with effects including the inhibition of TNF-alpha production. Our results suggest that inhibitors of matrix metalloproteinases may be of considerable therapeutic benefit in neuroinflammatory diseases.

Animals↗
PubMed1996

Overriding the brain's intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines.

Following the intracranial injection of lipopolysaccharide or during acute neuronal degeneration, there is a paucity of polymorphonuclear leukocyte recruitment to the brain parenchyma and a delay in monocyte recruitment. The present study investigates whether the injection of specific leukocyte chemoattractants into the murine central nervous system can override this intrinsic resistance. Recombinant alpha-(IL-8/NAP-1 MIP-2, IP-10) and beta-chemokines (MCP-1, RANTES) were injected into the murine hippocampus and leukocyte recruitment was assessed histologically. Injections were also made into the dermis of the hind flank for comparison. At doses of 1 microgram, MCP-1 was found to be the most potent monocyte chemoattractant in the brain parenchyma and skin with IP-10 and RANTES producing minimal monocyte recruitment to both sites. In contrast IL-8, and MIP-2 provoked dramatic polymorphonuclear leukocyte recruitment in both the central nervous system and skin. The polymorphonuclear leukocyte recruitment was associated with a breaching of the blood brain barrier that was particularly severe after MIP-2. Both L-8 and MIP-2 induced blood brain barrier breakdown could be attenuated by prior depletion of the circulating leukocytes. The regulation of polymorphonuclear leukocyte chemoattractants in the brain parenchyma during injury and infection is an important area for future studies.

Animals↗
PubMed1996

The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system.

Dendritic cells of the rat were studied immunohistochemically with MRC OX62 monoclonal antibody and using electron microscopy. In normal CNS, a small number of OX62+ cells was detected in the choroid plexus and meninges. These cells were absent from other CNS and peripheral nervous system sites studied. Dendritic cells were also studied in two models of immune-mediated inflammatory conditions in the CNS. These were: acute experimental allergic encephalomyelitis and aberrant delayed-type hypersensitivity lesions induced as a response to heat-killed bacillus Calmette-Guérin sequestrated behind the blood-brain barrier. In addition, a group of animals with a delayed-type hypersensitivity response was treated with dexamethasone to assess the effect of steroid treatment on T-cells and OX62+ cells in CNS lesions. Dendritic cells were present in many but not all lesions in acute experimental allergic encephalomyelitis and their numbers were small. In experimental allergic encephalomyelitis lesions, dendritic cells were found predominantly in perivascular cuffs, where they constituted approximately 2% of the total number of major histocompatibility complex class II+ cells. Some of these cells were also detected in the CNS parenchyma, close to the perivascular cuff. In contrast, dendritic cells were present in all delayed-type hypersensitivity lesions studied. Their number in delayed-type hypersensitivity lesions was significantly higher than in experimental allergic encephalomyelitis lesions. Numerous OX62+ cells were found, even in three-month-old lesions. Electron microscopy studies revealed that these cells were often in close contact with lymphocytes. There was no significant change in the density of OX62+ cells, IL2R+ cells and OX19+ T-cells in delayed-type hypersensitivity lesions after seven-day treatment with dexamethasone, although there was a considerable reduction in the number of CD45RA+ T-cells. The high numbers of dendritic cells found in the delayed-type hypersensitivity lesions may be important in contributing to the chronicity of the response. They may also initiate autoimmune responses to CNS antigens uncovered during bystander tissue damage which occurs as a consequence of aberrant delayed-type hypersensitivity responses.

Animals↗
PubMed1996

Evidence for an early inflammatory response in the central nervous system of mice with scrapie.

In Alzheimer's disease, the most prevalent of the neurodegenerative diseases, inflammation of the CNS contributes to the pathology and is a target for therapy. In contrast, the group of neurodegenerative conditions known as the Prion Diseases have been widely reported as lacking any inflammatory elements despite the many similarities between the pathologies of Alzheimer's Disease and Prion Diseases We have found evidence for an inflammatory component in mouse scrapie, characterized by microglial activation and T-lymphocyte recruitment, which appears long before any clinical signs of the disease and spreads along well-defined anatomical pathways. These observations emphasize the potential value of murine scrapie as a model for studying the inflammatory pathology of other neurodegenerative diseases.

Animals↗
PubMed1996

Activation and proliferation of murine microglia are insensitive to glucocorticoids in Wallerian degeneration.

Activation and proliferation of microglia are commonly described in the central nervous system after a wide range of insults, but the mechanisms that regulate their phenotype in vivo are still poorly understood. We have studied the effect that adrenalectomy and dexamethasone treatment have on the proliferation and activation of microglia during Wallerian degeneration of the optic nerve in BALB/c mice. We found that the onset and rate of microglia proliferation is independent of glucocorticoids. There was an increase in F4/80-positive cells 3 days after optic nerve crush, with a peak at 7 days, both in the optic nerve and its target, the superior colliculus. The numbers of F4/80-positive cells remained high up to 3 weeks after crush, the longest time point examined. We also found that up-regulation of F4/80 and the complement receptor type 3 and expression of major histocompatibility complex class II antigens were not affected by adrenalectomy or dexamethasone treatment. These observations show that, unlike microglia in vitro or peripheral macrophages, microglia do not readily respond to glucocorticoids, which could indicate a lack of or reduced expression of glucocorticoid receptor in these cells.

Animals↗
PubMed1996

Recombinant human adenovirus with rat MIP-2 gene insertion causes prolonged PMN recruitment to the murine brain.

Single injections of recombinant cytokines/chemokines into tissue have provided insights into their possible roles during the inflammatory response. Adenoviral technology may allow us to mimic the in vivo situation more closely, with protein generated in a continuous but transient fashion. Replication-deficient human type 5 adenovirus containing a rat macrophage inflammatory protein-2 (MIP-2) gene insertion and cytomegalovirus promoter was injected into the mouse brain to investigate the inflammatory response to continuous overproduction of MIP-2. Adenovirus with a LacZ gene insertion expressing beta-galactosidase was used as a control. At doses of 10(4) to 10(7) plaque-forming units, a minimal inflammatory response was detected to the LacZ virus, with leukocyte recruitment that was restricted to the injection site. A dose of 10(7) plaque-forming units of both the LacZ and the MIP-2 vector produced extensive transgene product expression that persisted for at least 7 days. Astrocytes, recognized by their morphology, were the predominant cell type expressing MIP-2 and beta-galactosidase. A dose of 10(7) plaque-forming units of MIP-2 vector caused dramatic polymorphonuclear leukocyte (PMN) recruitment to the brain parenchyma after 2 days. PMN recruitment was still observed after 4 and 7 days, but had become more localized to the injection site and was associated with numerous foam-like macrophages. At both 2 and 7 days the blood-brain barrier was breached in the region of leukocyte recruitment. Despite the extent of leukocyte recruitment there were no overt signs of neuronal degeneration or demyelination. Our findings demonstrate that continuous production of MIP-2 in the CNS results in persistent PMN recruitment to the brain parenchyma with no evidence of tachyphylaxis. The lack of PMN recruitment to the brain parenchyma following CNS injury may be a result of deficient production of PMN chemoattractants.

Adenoviruses, Human↗
PubMed1996

A comparison of leucocyte responses to heat-killed bacillus Calmette-Guérin in different CNS compartments.

We have previously shown that heat-killed bacillus Calmette-Guérin (BCG) injected into the CNS parenchyma does not produce a typical delayed-type hypersensitivity (DTH) response [23]. In this paper we have compared the initial leucocyte response in the CNS parenchyma, ventricles and skin to gain insight into the mechanisms by which the DTH response in the CNS might be controlled. We have found that 10(5) organisms of heat-killed BCG injected into either the CNS parenchyma or the lateral ventricles produced a rapid neutrophil response at the site of the injection, which was comparable with that in the skin. The neutrophil response resolved within the first week. Unlike the neutrophil response, the mononuclear phagocyte response in the CNS parenchyma was much smaller than that seen in the ventricles and the skin and it resolved within 4 weeks. Furthermore, the myelomonocytic response in the CNS parenchyma failed to clear the BCG. The acute inflammatory response in the choroid plexus/ventricles and skin developed with a similar time-course into a typical DTH response. After the first week, lesions at these two sites were composed predominantly of T-cells and macrophages. DTH lesions were still detected at both sites after 6 weeks. The failure of the immune system to recognize foreign antigens sequestrated in the CNS parenchyma may have significant implications especially in studies of inflammatory responses in the CNS of unknown origin.

Animals↗
PubMed1995

The unique characteristics of inflammatory responses in mouse brain are acquired during postnatal development.

The kinetics of leukocyte recruitment during acute inflammation in adult mouse brain differ from the stereotyped response occurring in non-CNS tissues; neutrophil recruitment is minimal and monocyte recruitment occurs after a 48 h delay. One aspect of the CNS microenvironment which may contribute to restricted leukocyte recruitment is the highly differentiated nature of resident CNS macrophages, the microglia. Thus we studied the inflammatory response to intracerebral injections of endotoxin in neonates in which microglia are less differentiated and resemble more closely macrophages of non-CNS tissues. Mice injected with endotoxin on the day of birth exhibited both neutrophil and monocyte recruitment to the parenchyma, but the response differed from that occurring in non-CNS tissues such as skin. Leukocyte recruitment was very slow, the mononuclear phagocyte response peaking 14 days after endotoxin injection. This sluggish inflammatory response was reminiscent of that previously described in fetal wounds. However, when endotoxin was injected into brains of 7-day-old neonates the inflammatory response resembled that seen in non-CNS tissues; i.e. prolific neutrophil recruitment and a brisk mononuclear phagocyte response. Thus the unusual inflammatory cell kinetics are a property of the mature CNS microenvironment; all signals necessary to support typical leukocyte recruitment are present in the brain by 7 days of age but the brain becomes able to restrict leukocyte immigration during subsequent postnatal development. Developmental changes in the host response to identical inflammatory challenges suggest a window during which the brain may be particularly vulnerable to inflammatory bystander damage.

Aging↗
PubMed1995

The rate of Wallerian degeneration in cultured neurons from wild type and C57BL/WldS mice depends on time in culture and may be extended in the presence of elevated K+ levels.

Wallerian degeneration of severed axons is delayed in C57BL/WldS mice. We have examined this further in cultured sympathetic, sensory and CNS neurons using superior cervical ganglion (SCG), dorsal root ganglion (DRG) and cerebellar granule neurons respectively from neonatal mice. We found that the time taken for the neurites to degenerate depends upon the length of time in culture before cutting, reaching a maximum by approximately 7 days when C57BL/WldS neurites survive for > 6 days after axotomy. The onset of degeneration could also be extended in SCG and DRG neurites from wild type C57BL/6J mice. After 7 days in culture these neurites normally degenerate within approximately 12-16 h of axotomy, but in the presence of raised K+ (50 mM) degeneration often did not begin until a further 2 days had lapsed. Under similar conditions degeneration of neurites from C57BL/WldS mice was also found to be further delayed, extending survival from approximately 5-6 days to > 7 days. The L-type Ca2+ channel blockers nifedipine (5 microM) and verapamil (10 microM) both blocked the effect of raised [K+], although not completely. Thapsigargin, which raises cytoplasmic [Ca2+], and the cAMP analogue 8-(4-chlorophenyl-thio)cAMP were also able to delay degeneration, but only when added 24 h prior to axotomy. These results show that it is possible to influence the course of Wallerian degeneration and that increases in levels of cytoplasmic Ca2+ can protect neurites from its onset.

Animals↗
PubMed1995

Persistence of neuromuscular junctions after axotomy in mice with slow Wallerian degeneration (C57BL/WldS).

The present study was undertaken to examine the fate of neuromuscular junctions in C57BL/WldS mice (formerly known as OLA mice) after nerve injury. When a peripheral nerve is injured, the distal axons normally degenerate within 1-3 days. For motor axons, an early event is deterioration of motor nerve terminals at neuromuscular junctions. Previously, the vulnerability of motor terminals has been attributed either to a 'signal' originating at the site of nerve injury and transported rapidly to the terminals or to their continual requirement for essential maintenance factors synthesized in the motor neuron cell body and supplied to the terminals by fast axonal transport. Mice of the WldS strain have normal axoplasmic transport but show an abnormally slow rate of axon and myelin degeneration. Structure and function are retained in the axons of distal nerve stumps for several days or even weeks after nerve injury in these mice. The results of the present study show that WldS neuromuscular junctions are also preserved and continue to release neurotransmitter and recycle synaptic vesicle membrane for at least 3 days and in some cases up to 2 weeks after nerve injury. Varying the site of the nerve lesion delayed degeneration by approximately 1-2 days per centimetre of distal nerve remaining. These findings suggest that the mechanisms of nerve terminal degeneration after injury are more complex than can be accounted for simply by the failure of motor neuron cell bodies to supply their terminals with essential maintenance factors. Rather, the data support the view that nerve section normally activates cellular components or processes already present, but latent, in motor nerve endings, and that in WldS mice either the trigger or the cellular response is abnormal.

Aging↗
PubMed1995

Radiation-induced reductions in macrophage recruitment have only slight effects on myelin degeneration in sectioned peripheral nerves of mice.

Macrophage recruitment into the distal nerve stump of the cut or crushed sciatic or saphenous nerves of C57BL/6J mice was reduced by prior whole body irradiation. This procedure was successful in keeping the numbers of cells stained with the mouse macrophage-specific antibody F4/80 to the levels found in unsectioned nerves. Quantitative image analysis of immunostained sections showed that the rate of loss of myelin basic protein was identical in nerves from irradiated and unirradiated mice up to 5 days but thereafter was slower in macrophage-deprived nerves. Similar analysis of semithin sections stained with toluidine blue detected more undegenerated myelin in the nerves from irradiated mice 10 days after operation. Quantitative counts made from electron micrographs of the sectioned nerves at 7 days also showed slightly less extensive myelin breakdown in the nerves from irradiated mice. Complete removal of myelin from some Schwann cells can occur without macrophages, but macrophages accelerate the removal of myelin in the later stages of Wallerian degeneration. It is concluded that there are two phases to the breakdown of myelin in peripheral nerves undergoing Wallerian degeneration: an initial stage entirely dependent on the activity of Schwann cells and a later stage dependent on both Schwann cells and the presence of macrophages.

Animals↗
PubMed1995

Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammagen or during acute neuronal degeneration.

The acute inflammatory response in the murine CNS is different from that observed in other tissues. Few polymorphonuclear leukocytes are recruited to the brain parenchyma and there is a delay in the recruitment of monocytes. Leukocyte recruitment to sites of inflammation is dependent on adhesion molecules expressed on the endothelium. The atypical kinetics of leukocyte recruitment to the CNS may be the result of deficient or delayed adhesion molecule expression on the cerebral endothelium. Using immunohistochemistry, the present study demonstrates that following the intracranial injection of a proinflammagen, lipopolysaccharide, or following acute neuronal degeneration elicited with kainic acid, the adhesion molecules ICAM-1 and VCAM were readily upregulated on cerebral endothelium in a time course comparable with that demonstrated on non-CNS endothelium. Both molecules were expressed on vessels, irrespective of their size, at 24 h after kainic acid or 6 h after lipopolysaccharide injection but leukocyte recruitment was negligible. The expression of ICAM-1 was demonstrated not only on endothelium but also on microglia especially in response to nerve terminal degeneration. PECAM was constitutively expressed at high levels on cerebral endothelium and did not change during brain injury. However, PECAM was induced on astrocytes after lipopolysaccharide injection or during acute neuronal degeneration, the latter providing a particularly strong stimulus. This study indicates that the expression of these adhesion molecules on CNS endothelium is neither deficient or delayed and that they are unlikely to be limiting factors in leukocyte recruitment to the CNS.

Animals↗
PubMed1995

Demyelination in the central nervous system following a delayed-type hypersensitivity response to bacillus Calmette-Guérin.

We describe here a model of delayed-type hypersensitivity response in the CNS directed against a non-CNS antigen. The results presented in this paper show that bacillus Calmette-Guérin sequestrated behind the blood-brain barrier provokes an immune-mediated assault leading to bystander myelin damage. The delayed-type hypersensitivity response was induced by the intracranial injection of heat-killed bacillus Calmette-Guérin followed by subcutaneous immunization two to six weeks later. A single intracranial injection of bacillus Calmette-Guérin resulted in a rapid myelomonocytic response which persisted for approximately two weeks. By four weeks the inflammatory cells were no longer detected. Serum proteins were also excluded from the CNS parenchyma at this time. However, immunohistochemical staining with anti-bacillus Calmette-Guérin antiserum revealed the presence of bacillus Calmette-Guérin debris at the site of the original intracranial injection, indicating that the inflammatory response failed to clear the mycobacterium fully. Following peripheral sensitization with bacillus Calmette-Guérin in complete Freund's adjuvant, a strong delayed-type hypersensitivity response was detected at the site of bacillus Calmette-Guérin deposits in the CNS. An extensive inflammatory lesion was spread over a large area of the dorsal hippocampus. The lesion was composed predominantly of mononuclear phagocytes and T cells. Staining with anti-myelin basic protein antiserum showed bystander myelin damage. Delayed-type hypersensitivity responses were studied over several months and were still detected in the CNS five months after peripheral immunization.

Animals↗
PubMed1995

Inflammation in the nervous system.

Earlier studies on inflammation in the CNS have largely focused on conditions with an immune component. Recent evidence has emerged, however, that the innate, acute inflammatory response in the CNS parenchyma is quite unlike that in other tissues. The meninges and ventricular compartments show more typical responses, as does the parenchyma of the brain in immature animals. It is becoming apparent that the cells of the mononuclear phagocyte lineage dominate inflammatory responses in the CNS parenchyma.

Animals↗