Biomedical subjects

L Rosén

Publications and source records attributed to L Rosén.

At least 19 recordsLinked to original sources

PubMed2001

Myointimal hyperplasia and sympathetic reinnervation following local cold injury and rapid rewarming in the rabbit central ear artery.

BACKGROUND: Functional and pathological improvements following rapid rewarming in 42 degrees C water was compared with alterations following slow thawing at room temperature (22 degrees C) after frostbite (-9 degrees C, 15 minutes) in vivo of the rabbit central ear artery. METHODS: Following two to ten weeks of in vivo regeneration, vascular segments were tested in vitro. Maximal and dose-dependent isometric contractions were induced by exogenous noradrenaline. Sympathetic nerves in the vascular wall were stained with glyoxylic acid. Vascular ring segments were stained with haematoxylin and eosin. RESULTS: Following slow thawing, the total uptake, the K+ evoked and the spontaneous release of [3H]noradrenaline in the sympathetic nervous system were strongly reduced two weeks after freezing, with a subsequent increase to control level within 3-4 weeks. After rapid rewarming the total uptake, the spontaneous release and the K+ evoked release of [3H]noradrenaline commenced earlier such that after ten weeks the level was twice as high as following slow rewarming. The glyoxylic acid induced catecholamine fluorescence in sympathetic nerves, revealed an earlier regeneration after rapid rewarming. Haematoxylin and eosin-stained segments revealed less intimal hyperplasia three to 20 weeks after rapid rewarming than after slow thawing. CONCLUSION: Rapid rewarming of in vivo frozen arteries in warm water (42 degrees C) did not prevent immediate vasoparalysis and degeneration of sympathetic nerves. However, nerve regeneration occurred earlier and with higher tissue nerve densities as compared to tissue that had been slowly rewarmed. Myointimal hyperplasia was less pronounced after rapid rewarming. Abnormal sympathetic nerve function and myointimal hyperplasia, as observed in this study, may contribute to a greater understanding of sequelae in the human body following frostbite.

Adrenergic Fibers↗

PubMed2000

Outcome after catheter-directed thrombolysis of occluded prosthetic femoropopliteal bypasses. A prospective study.

PURPOSE: To evaluate the outcome after catheter-directed thrombolysis of occluded femoropopliteal prosthetic bypasses with the distal anastomosis above the knee. MATERIAL AND METHODS: Twenty-one patients were included in this prospective study. End-hole catheters, a bolus dose and continuous infusion of recombinant tissue-plasminogen activator (rt-PA) were used, with a median total dose of 10 mg (range 7-20 mg). RESULTS: With an intra-thrombotic position of the catheter, total or subtotal lysis was obtained in 19 of 21 patients (90%). No serious complications occurred. In 9 patients, the stenoses were successfully treated with balloon angioplasty (PTA, n=5), local thrombectomy/extension of bypass (n=3), or with a new bypass (n=1). After a median observation time of 18 months (6-24), 5 patients had open bypass. Re-occlusion occurred in all (6/6) bypasses in which no flow-limiting lesion was discovered, in all (4/4) bypasses treated twice with thrombolysis, as well as in all bypasses in which stenoses had not been adequately treated (3/3). One bypass re-occluded immediately due to poor runoff. CONCLUSION: In the present study, 19/21 infra-inguinal prosthetic bypasses were successfully treated with catheter-directed thrombolysis. However, re-occlusion often took place, especially in bypasses without flow-limiting lesions. If re-occlusion occurs in a bypass in which no stenoses were revealed during the primary thrombolysis procedure, a second catheter-directed thrombolytic treatment does not seem to be warranted. Our results confirm that treatment of flow-limiting lesions is a prerequisite for maintaining patency.

Aged↗

PubMed1999

Effects of nitric oxide inhibition on the spread of biotinylated dextran and on extracellular space parameters in the neostriatum of the male rat.

Volume transmission in the brain is mediated by the diffusion of neurotransmitters, modulators and other neuroactive substances in the extracellular space. The effects of nitric oxide synthase inhibition on extracellular space diffusion properties were studied using two different approaches, the histological dextran method and the real-time iontophoretic tetramethylammonium method. The spread of biotinylated dextran (mol. wt 3000) in the extracellular space was measured morphometrically following microinjection into the neostriatum of male rats. Two parameters were used to describe the spread of biotinylated dextran in brain tissue, namely, total volume of spread and the mean grey value. The nonspecific nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (10-100 mg/kg) and NG-monomethyl-L-arginine acetate (30-200 mg/kg) decreased the total volume of spread of dextran in a dose-dependent manner. 7-Nitroindazole monosodium salt (50-100 mg/kg), a specific neuronal nitric oxide synthase inhibitor, did not change the total volume of spread of dextran. Using the tetramethylammonium method, the extracellular space diffusion properties can be described by the volume fraction (alpha = extracellular space volume/total tissue volume), tortuosity lambda (lambda2 = free diffusion coefficient/apparent diffusion coefficient in tissue), and non-specific uptake kappa' [Nicholson C. and Syková E. (1998) Trends Neurosci. 21, 207-215]. Nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (50 mg/kg) had relatively little effect on volume fraction and tortuosity, and no changes were observed after NG-monomethyl-L-arginine acetate (20 mg/kg) or 7-nitroindazole monosodium salt (100 mg/kg) treatment. A substantial increase was found only in non-specific uptake, by 13% after NG-nitro-L-arginine methyl ester and by 16% after NG-monomethyl-L-arginine acetate, which correlates with the decreased total volume of spread of dextran observed with the dextran method. NG-Nitro-L-arginine methyl ester treatment (100 mg/kg) decreased striatal blood flow and increased mean arterial blood pressure. The changes in dextran spread and non-specific uptake can be explained by an increased capillary clearance following the inhibition of endothelial nitric oxide synthase, as neuronal nitric oxide synthase inhibition had no effect. The observed changes after non-specific nitric oxide synthase inhibition may affect the extracellular space concentration of neurotransmitters and modulators, and influence volume transmission pathways in the central nervous system by increased capillary and/or cellular clearance rather than by changes in extracellular space diffusion.

Animals↗

PubMed1999

Early and late functional and histopathological perturbations in the rabbit ear-artery following local cold injury.

BACKGROUND: These experiments aimed to study the in vivo short and long term neurovascular regeneration after frostbite. METHODS: The rabbit central ear-artery was used as the experimental model. The effects on the noradrenergic innervation of the artery were measured in isolated vascular ring segments the first day and 2, 3-4, and 8-10 or 10-20 weeks following freezing at -9 degrees C or -18 degrees C for 15 min with slow rewarming for 7 min at room temperature. RESULTS: Two days after freezing the sympathetic nerves were completely degenerated, as observed with glyoxylic acid-induced fluorescence. The vascular isometric tension responses to exogenous noradrenaline and endogenously released noradrenaline by electrical stimulation in vitro were abolished. A varying degree of necrosis of the vascular wall was observed. Two weeks after freezing at -18 degrees C in vitro responses to exogenous noradrenaline and electrical stimulation were still abolished, then gradually approaching control levels after 10-20 weeks of in vivo regeneration. Eight and 10 weeks after injury at -9 degrees C increased vascular tension responses to exogenous noradrenaline was found. In spite of a long regeneration period the total uptake and the spontaneous and K+ (75 mM) evoked releases of [3H]noradrenaline were persistently decreased after frostbite at -18 degrees C, but they were regenerated to control levels already 10-20 weeks after -9 degrees C. Regeneration of noradrenergic nerve function, expressed as [3H]noradrenaline uptake and release and responsiveness to electrical stimulation, expressed as vascular contraction, was slower than the regeneration of the vascular smooth muscle. Myointimal hyperplasia developed in response to -9 degrees C and -18 degrees C frostbite. The uptake and the K+ evoked release of [3H]noradrenaline were particularly sensitive parameters for autonomic nerve function. CONCLUSIONS: The present findings may demonstrate important neurovascular reactions to local frostbite and may explain human sequelae following frostbite.

Adrenergic Fibers↗

PubMed1999

Morphological abnormalities revealed after successful intra-arterial thrombolysis of infra-inguinal native arteries and bypasses.

PURPOSE: To characterise morphological abnormalities depicted after successful intra-arterial thrombolysis; to determine whether these differed in infra-inguinal native arteries and bypasses; and to evaluate whether balloon angioplasty was an appropriate treatment of stenoses in the acute phase after thrombolysis. MATERIAL AND METHODS: Patient records, radiology records, and angiograms from 47 patients with acute or subacute occlusions of infra-inguinal arteries (n = 21) or bypasses (n = 26) successfully treated with continuous intra-arterial infusion of streptokinase, urokinase or tissue plasminogen activator were retrospectively reviewed. RESULTS: Angiographic morphological abnormalities were depicted in 18 of 21 arteries (86%) and in 23 of 26 bypasses (88%), the most common abnormality being stenoses. Haemodynamically significant stenoses were found in 15 arteries (71%) and 18 bypasses (69%). The majority of the stenoses were successfully treated with balloon angioplasty, both in native arteries (12/15; 80%) and in bypasses (14/18; 78%). CONCLUSION: Morphological abnormalities are most often shown after successful intra-arterial thrombolysis in arteries, autogenous and non-autogenous bypasses. In all types of conduits, stenoses are the most commonly revealed lesion, which in the majority of cases can be treated with balloon angioplasty. Short-term outcome after catheter-directed thrombolysis and angioplasty seems fair.

Adult↗

PubMed1998

Analytic decision-making in patients with critical limb ischaemia.

Patients with critical limb ischaemia have a relative short life expectancy. However, if the limb can be preserved or amputation postponed for at least 1-2 years there can be justification for revascularisation if it is possible. Published Scandinavian data indicate that of those operated on about one-third are primarily amputated and two-third revascularised. At least one-third in the revascularisation group are subjected to secondary amputation within six months, and about 50% are alive with the limb intact. Hence, prediction of successful reconstruction should be amended to reduce costs and reduce burden to the patients. In order to achieve statistical models, which preoperatively could predict outcome with an acceptable diagnostic accuracy, national as well as international cooperation with standardisation of predictors and appropriate use of statistical models should be strived for. Prediction, based on a statistical model, is always associated with some uncertainty, and will never replace qualified clinical judgement.

Amputation, Surgical↗

PubMed1996

[Local thrombolytic treatment of peripheral arterial thrombosis and embolism].

Local intra-arterial low-dose thrombolysis has become a therapeutic alternative for acute and subacute occlusion of vascular grafts and native vessels in the lower limbs. The series comprises 31 patients treated with Streptokinase as thrombolytic agent. Complete primary thrombolysis was achieved in 20 patients, whereas in 11 patients the outcome was only partially successful or a failure. Vascular stenoses were considered to precipitate thrombosis in 18 cases, and prompted percutaneous transluminal angioplasty after thrombolysis. Two-year patency was 48% (30-66%) in the total series and 74% (56-92%) among the patients with successful primary thrombolysis. There were no major complications. Five patients sustained local inguinal haemorrhage, of whom three required surgical revision. Local intra-arterial thrombolysis is an elaborate procedure associated with potential hazardous complications. It should be carried out in institutions with radiological and vascular surgical expertise.

Adult↗

PubMed1996

[Intra-arterial thrombolysis in peripheral bypass and arterial occlusions. Results and predictive factors for thrombolysis].

The purpose of the study was to reveal the association between successful intra-arterial thrombolysis in peripheral arterial and graft occlusions and the following factors: sex, age, symptoms, duration of symptoms, length of occlusion, conduit type, runoff and catheter localisation. Forty-six patients were treated with continuous intra-arterial infusion of streptokinase. Twelve patients were given tissue plaminogen activator (tPA). In the streptokinase-group successful lysis was achieved in 27 of 46 patients (59%). A significant association was found between successful thrombolysis and good runoff (p < 0.01). Catheter position above the occlusion resulted in lysis in only 1 of 11 patients. Lysis was achieved in nine of 12 patients (75%) treated with tPA. In this study, good runoff and intrathrombotic infusion were almost prerequisites for obtaining a positive immediate outcome. Other factors were less important.

Aged↗

PubMed1996

Nerve conduction velocity in human limbs with late sequelae after local cold injury.

Cold-induced neuropathy may play a dominant role in the long-term sequelae with cold sensitivity after local cold injuries (LCIs). Somatosensory functions were assessed and nerve conduction velocity (NCV) and motor distal delay (MDD) were measured in the limbs of 31 Norwegian former soldiers with persistent cold intolerance 3-4 years after the primary LCI. NCV measurements were performed in 24 lower and 16 upper extremities. NCV was related to degree of overall subjective complaints quantified by means of a visual analogue scale (VAS). Motor (MNCV) and sensory conduction velocity (SNCV) in the lower extremities and SNCV in the hands were significantly decreased compared with controls. MDD was pathologically increased in the feet. NCV of the forearms ranged from normal to significant reduction. The more pronounced effect on the lower extremities may be caused by deeper cooling of the calves compared with forearms for several reasons. No significant associations were found between VAS and NCV except for the right median nerve. NCV measurements may provide objective findings in cold-injured patients and in those with few or no conspicuous clinical signs.

Adult↗

PubMed1996

Do routinely registered preoperative data provide prognostic information on the short-term outcome of distal bypass surgery?

One hundred and thirty and patients were operated on with unilateral distal bypass procedures for critical ischemia. Fifty-one patients (39%) ended up with graft occlusion or required major amputation within six months after reconstruction. Two-year graft patency was 38%. These rather disappointing results may be partly ascribed to inadequate preoperative selection of patients. Logistic regression model was used to assess whether the independent variables age, gender, diabetes mellitus, smoking, ankle-brachial pressure index (ABI), type of graft, coronary heart disease (CHD), previous vascular operation and site of distal anastomosis were associated with the outcome amputation and graft occlusion six months after reconstruction. CHD, type of graft, ABI and the location of distal anastomosis were significantly associated with outcome. The odds for amputation or occlusion was 2.4 times higher in the CHD group, 4 times higher if the anastomosis was located to the peroneal artery and 2.6 times higher for synthetic grafts. The logistic regression model was statistical significant (p = 0.03). However, the model did not aid sufficiently in the prediction of outcome, since one third was erroneously classified as success or failure. Cox's proportional hazard regression was employed to estimate the influence of the independent variables on graft patency. Favorable patency was found for those with distal anastomosis located to the tibial arteries, the non-CHD group and for higher ABI values. There was a trend towards significance for better patency in the autogenous vein group (p = 0.06). Although combinations of risk factors usable for preoperative prediction of the likelihood of graft failure, appropriate selection models of patients suitable for distal bypass operation have to be improved, to minimize the number of failed procedures.

Aged↗

PubMed1994

On the plasticity of the cerebellar renin-angiotensin system: localization of components and effects of mechanical perturbation.

This study focuses on the renin-angiotensin system (RAS) in the cerebellar cortex and changes within this system after mechanically induced cerebellar injury. Using radioactive and non-radioactive in situ hybridization and immunocytochemistry angiotensinogen mRNA, angiotensinogen, angiotensin II and, for the first time, N-terminal angiotensin fragment (1-7) immunoreactivities, respectively, were demonstrated in the rat cerebellum. Angiotensinogen mRNA and angiotensinogen immunoreactivity (IR) were both present in glial cell populations of all layers, especially in the Purkinje and granular cell layers and within the cerebellar nuclei. Angiotensin II IR was demonstrated in glial cell populations in all layers using a monoclonal angiotensin II antibody, while with a polyclonal angiotensin II antiserum (Denise) some Purkinje cell bodies were labelled. After lesioning the cerebellar cortex mechanically by an injection cannula a strong increase in angiotensinogen gene expression as well as in angiotensin II and angiotensin (1-7) immunoreactivities were observed in the glial cell populations. Furthermore, putative Bergmann glial processes, as indicated from the morphological appearance became strongly angiotensin II and angiotensinogen immunoreactive in the region close to the mechanically induced lesion. It could inter alia be demonstrated for the first time using confocal laser microscopy of ANG II IR and GFAP IR that ANG II in vivo in the intact cerebellar cortex is present in astroglial processes in the molecular layer and presumably secreted into the extracellular space in form of small spheric bodies and/or taken up by other cell types. In contrast, the N-terminal fragment angiotensin (1-7) IR was restricted to the glial cell populations and appeared only after the lesion event. Thus, it is suggested that the cerebellar RAS shows marked changes in response to mechanically induced lesions. The expression of angiotensinogen as well as the production of angiotensinogen IR and angiotensin II like IR is even after mechanical lesion restricted to astrocytes, i.e., cerebellar astrocytes and putative Bergmann glial cells, and in case of immunoreactivities it spreads to the radially oriented Bergmann glial processes in the molecular layer.

Angiotensin I↗

PubMed1994

[Electromagnetic therapy for patients with intermittent claudication--is it effective?].

A treatment based on electromagnetic principles (Elmedistraal) has been tested on 12 patients with intermittent claudication. What initiated this investigation was the publicity in the media around this treatment and its supposedly positive effect on peripheral circulation. 12 patients received ten placebo and ten active treatments. The patients were thus their own control. We looked for changes in clinical signs, ankle/arm pressure index (ultrasound Doppler) and maximal walking distance (treadmill). The patients reported changes in symptoms by means of a visual analog scale. In this study neither subjective nor objective effects of treatment with Elmedistraal could be documented in patients with claudication.

Aged↗

PubMed1994

Chronic continuous infusion of nicotine increases the disappearance of choline acetyltransferase immunoreactivity in the cholinergic cell bodies of the medial septal nucleus following a partial unilateral transection of the fimbria fornix.

Previous studies have demonstrated that chronic continuous nicotine treatment via minipumps partially protects against mechanically induced degeneration of the nigrostriatal dopamine neurons in the male Sprague-Dawley rat. In the present study we investigated how a 4-week continuous infusion with (-)-nicotine via minipumps implanted subcutaneously in the male Sprague-Dawley rat (0.125 mg/kg-1 h-1) influences the anterograde and retrograde changes occurring in the septohippocampal cholinergic neurons following a unilateral transection of the fimbria fornix. Choline acetyltransferase and acetylcholinesterase immunocytochemistry was performed in combination with computer-assisted morphometry and microdensitometry. Measurements of choline acetyltransferase enzyme activity was performed in the dorsal hippocampus. The chronic nicotine infusion significantly increased the disappearance of the choline acetyltransferase immunoreactive nerve cell area within the medial septal nucleus of the lesioned side. However, the disappearance of the acetylcholinesterase immunoreactive nerve terminals within the dentate gyrus (molecular layer) and of choline acetyltransferase enzyme activity within the dorsal hippocampus was not found to be influenced by the chronic nicotine infusion. Thus, chronic infusion of (-)-nicotine does not appear to exert any protective activity on mechanically injured septohippocampal cholinergic neurons but may instead increase their dysfunction. In comparison with the dopaminergic neurons it may therefore be that the continuous chronic nicotine exposure does not lead to sufficient desensitization of the nicotinic cholinoceptors of the cholinergic neurons to reduce the chronic influx of sodium and calcium ions via the nicotinic ion channels and thus intraneuronal calcium levels and energy demands.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗

PubMed1994

The dopamine D2 antagonist remoxipride acts in vivo on a subpopulation of dopamine D2 receptors.

Dopamine D2 receptors were inactivated by N-ethoxycarbonyl-2-ethoxy-1,2,-dihydroxy-quinoline (EEDQ) (6 mg/kg i.p.). The reduction in dopamine receptors was monitored by quantitative receptor autoradiography using [125I]iodosulpiride or [3H]raclopride as radioligands. Pretreatment of male rats with haloperidol (0.3-3 mumol/kg i.p.) produced a dose-related, complete protection against the decrease in [125I]iodosulpiride binding induced by EEDQ in the dorsal and ventral striata and in all cortical areas examined. Raclopride (0.25-10 mumol/kg i.p.) produced the same pattern of effect as haloperidol but had a weaker effect. In contrast, remoxipride (1-40 mumol/kg i.p. or s.c.) only produced a partial protection against the dopamine D2 receptor inactivation by EEDQ. The results in the EEDQ test were related to the potency to block d-amphetamine-induced hyperlocomotion and the ability to induce bar-test catalepsy in the rat. The potencies in the behavioural tests were found to correspond to the in vivo occupancy for dopamine D2 receptors as evaluated by the EEDQ-induced decrease in D2 binding. However, remoxipride differed from both haloperidol and raclopride by showing a much reduced occupancy of dopamine D2 receptors at doses with behaviourally equipotent effects. The results support earlier suggestions that remoxipride in vivo may act on a subpopulation of dopamine D2 receptors.

Animals↗

PubMed1994

Mapping and computer assisted morphometry and microdensitometry of glucocorticoid receptor immunoreactive neurons and glial cells in the rat central nervous system.

By means of a monoclonal mouse immunoglobulin G2a antibody against the rat liver glucocorticoid receptor and the indirect immunoperoxidase technique, the distribution of glucocorticoid receptors in neuronal and glial cell populations was mapped in the central nervous system of the male rat. The mapping was complemented by computer-assisted morphometric and microdensitometric evaluation of glucocorticoid receptor immunoreactivity in many brain regions. The quantitative analysis allowed us to achieve for the first time an objective characterization of glucocorticoid receptor distribution in the CNS, thus avoiding the ambiguities of previous mapping studies based on subjective evaluations. In addition, a taxonomic analysis of central nervous system regions containing glucocorticoid receptor immunoreactivity was carried out utilizing the quantitative parameters obtained in the morphometric evaluation. Nuclei of neuronal and glial cells containing glucocorticoid receptor immunoreactivity were detected in a widespread, but still highly heterogeneous, fashion in the central nervous system, underlining the view that glucocorticoids can control a large number of central nervous system target cells via effects on gene expression. Many nerve cell populations have been shown to contain substantial amounts of nuclear glucocorticoid receptor immunoreactivity, whereas only a low density of glial cells, in both gray and white matter, show nuclear glucocorticoid receptor immunoreactivity. Thus, in most brain areas, the major target for glucocorticoids appears to be the nerve cells. Interestingly, an inverse correlation was found in the regional density of glucocorticoid receptor-immunoreactive nerve and glial cells, suggesting that glucocorticoids may influence a brain area either via glial cells or, more frequently, via nerve cells. The results on mapping highlight the impact of glucocorticoids in areas both traditionally and not traditionally involved in stress responses. The distribution of glucocorticoid receptor immunoreactivity also emphasizes a role of glucocorticoids in the regulation of the afferent regions of the basal ganglia and the cerebellar cortex, and of both afferent and efferent layers of the cerebral cortex. Glucocorticoid receptor immunoreactivity is widely distributed over the thalamus, probably leading to modulation of activity in the various thalamocortical pathways transmitting inter alia specific sensory information to the cerebral cortex. Many unspecific afferents to the cerebral cortex are potentially regulated by glucocorticoid receptors such as the noradrenaline and 5-hydroxytryptamine afferents, since their nerve cells of origin contain strong glucocorticoid receptor immunoreactivity. Eight brain regions involving sensory, motor and limbic areas were shown to have a similarity with regard to glucocorticoid receptor-immunoreactive parameters at the level of 95%. The density of glucocorticoid receptor-immunoreactive nerve cells appeared to be the main factor in determining such a very high level of similarity. Overall, our results emphasize that glucocorticoids may appropriately tune networks of different areas to obtain optimal integration and in this way improve survival of the animal under challenging conditions.

Adrenalectomy↗

PubMed1993

Photochemically induced focal cerebral ischemia in rat: time dependent and global increase in expression of basic fibroblast growth factor mRNA.

Induction of basic fibroblast growth factor (bFGF) mRNA expression was studied in a Rose bengal induced focal cerebral ischemia during a time course of 2, 4, 24, 72 h and 7 days. Focal cerebral ischemia induced by Rose bengal resulted in a global upregulation in bFGF gene expression at the 24 h time-interval. This upregulation in bFGF gene expression was due to an upregulation in glial bFGF expression in most of the areas studied as seen by means of non-radioactive in situ hybridization in combination with immunocytochemistry for glial fibrillary acidic protein. However, in the piriform cortex a putative neuronal upregulation of bFGF could be detected by combination of non-radioactive in situ hybridization, immunohistochemistry for glial fibrillary acidic protein and nuclear staining with Neutral red. Semiquantitative data concerning bFGF mRNA expression were obtained by use of computer-assisted microdensitometry and revealed substantial increases in bFGF mRNA expression in the cingulate cortex, the neostriatum, a 1 mm marginal zone close to the external capsule and the olfactory tubercle at bregma levels 1 to 2 mm rostral to the lesion. No changes in bFGF gene expression were seen in field CA1 of Ammon's horn on the lesioned side and in dentate gyrus at bregma levels between -2.12 to -3.30 mm. We observed significant changes in bFGF upregulation in the caudate putamen, the piriform cortex and the amygdaloid region and the frontoparietal cortex at bregma levels -2.12 to -3.30 mm. These data indicate that photochemically induced focal cerebral ischemia leads to an early and global response in bFGF gene expression, which is due to an upregulation mainly in astrocytes. The observed widespread upregulation of the bFGF gene transcription rostral and caudal to the lesion is suggested to be due in part to neuronal glutaminergic connections between the areas investigated and in part due to increases in extracellular fluid signals (volume transmission).

Animals↗

PubMed1993

The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway.

We studied the ability of the vigilance-promoting drug modafinil to modulate the anterograde and retrograde changes in tyrosine hydroxylase (TH) immunoreactivity and in dopamine (DA) stores in the nigro-neostriatal DA neurons, following a partial hemitransection of this ascending DA system, using a combined morphometrical, biochemical and behavioural analysis. Modafinil was given daily i.p. in doses of 10-100 mg/kg, starting 15 min after the lesion, and the partially hemitransected rats were killed 2 weeks later. Changes in TH-immunoreactive nerve cell bodies and nerve terminals induced by the partial hemitransection were studied in the substantia nigra and neostriatum in combination with image analysis. The substantia nigra and neostriatum were also subjected to biochemical analysis of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Modafinil treatment dose-dependently (10-100 mg/kg) counteracted the hemitransection-induced disappearance of nigral TH-immunoreactive nerve cell body profiles and neostriatal TH-immunoreactive nerve terminal profiles. A 2-week treatment with 100 mg/kg of modafinil also counteracted the hemitransection-induced depletion of DA stores in the neostriatum and the ventral midbrain. Moreover, the repeated daily treatment with modafinil (100 mg/kg) protected against the hemitransection-induced disappearance of striatal 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and noradrenaline levels. Striatal DA function was analysed by studying apomorphine-induced (1 mg/kg, s.c.) ipsilateral rotational behaviour 4 and 11 days after the operation. A marked dose-dependent reduction of ipsilateral rotational behaviour was demonstrated after the daily modafinil treatment in the partially hemitransected rats. In another model involving unilateral nigral microinjections of 6-hydroxydopamine, acute (one single dose) modafinil (100 mg/kg) did not affect the contralateral rotational behaviour induced by apomorphine (0.05 mg/kg s.c.), when given 30 min before the apomorphine. Taken together, morphological, neurochemical and behavioural evidence has been obtained that anterograde and retrograde changes induced in the DA stores and TH immunoreactivity of the nigro-neostriatal DA neurons by a partial hemistransection are counteracted by modafinil in a dose dependent way with 100 mg/kg producing a significant protective action against impairment of DA transmission. The results of this study open up the possibility that modafinil may protect against the anterograde and retrograde degeneration of nigrostriatal DA neurons seen after mechanically induced injury.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1993

Protective actions of human recombinant basic fibroblast growth factor on MPTP-lesioned nigrostriatal dopamine neurons after intraventricular infusion.

Basic fibroblast growth factor (bFGF, FGF-2) is a trophic factor for neurons and astrocytes and has recently been demonstrated in the vast majority of dopamine (DA) neurons of the ventral midbrain of the rat. Potential neuroprotective actions of FGF-2 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model have also been reported. The actions of the FGF-2 have now been further analyzed in a combined morphological and behavioural analysis in the MPTP model of the adult black mouse, using a continuous human recombinant FGF-2 (hrFGF-2) intraventricular (i.v.t.) administration in a heparin-containing (10 IU heparin/ml) mock cerebrospinal fluid (CSF) solution. Tyrosine hydroxylase (TH) immunocytochemistry in combination with computer assisted microdensitometry demonstrated a counteraction of the MPTP-induced disappearance of neostriatal TH-immunoreactive (ir) nerve terminals following the FGF-2 treatment. Unbiased estimates of the total number of nigral TH ir neurons, using stereological methods involving the optical disector (Olympus), showed that the MPTP-induced reduction in the number of nigral TH ir nerve cell bodies counterstained with cresyl violet (CV; by 56%) was partially counteracted by the FGF-2 treatment (by 26%). The behavioral analysis demonstrated an almost full recovery of the MPTP-induced reduction of the locomotor activity after FGF-2 treatment. This action was maintained also 1 week after cessation of treatment. The hrFGF-2 produced an astroglial reaction as determined in the lateral neostriatum and in the substantia nigra (SN) far from the site of the infusion, indicating that the growth factor may have reached these regions by diffusion to activate the astroglia. Immunocytochemistry revealed FGF-2 immunoreactivity (IR) in the nuclei of the astroglia cell population in the dorsomedial striatum and the microdensitometric and morphometric evaluation demonstrated an increase in the number, but not in the intensity, of these profiles on the cannulated side, suggesting the possibility that hrFGF-2 stimulates FGF-2 synthesis in astroglial cells with low endogenous FGF-2 IR. These results indicate that hrFGF-2, directly and/or indirectly via astroglia, upon i.v.t. infusion exerts trophic effects on the nigrostriatal DA system and may increase survival of nigrostriatal DA nerve cells exposed to the MPTP neurotoxin

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗