Biomedical subjects

F P Hamers

Publications and source records attributed to F P Hamers.

At least 19 recordsLinked to original sources

PubMed2002

Injury-induced class 3 semaphorin expression in the rat spinal cord.

In this study we evaluate the expression of all members of the class 3 semaphorins and their receptor components following complete transection and contusion lesions of the adult rat spinal cord. Following both types of lesions the expression of all class 3 semaphorins is induced in fibroblast in the neural scar. The distribution of semaphorin-positive fibroblasts differs markedly in scars formed after transection or contusion lesion. In contusion lesions semaphorin expression is restricted to fibroblasts of the meningeal sheet surrounding the lesion, while after transection semaphorin-positive fibroblast penetrate deep into the center of the lesion. Two major descending spinal cord motor pathways, the cortico- and rubrospinal tract, continue to express receptor components for class 3 semaphorins following injury, rendering them potentially sensitive to scar-derived semaphorins. In line with this we observed that most descending spinal cord fibers were not able to penetrate the semaphorin positive portion of the neural scar formed at the lesion site. These results suggest that the full range of secreted semaphorins contributes to the inhibitory nature of the neural scar and thereby may inhibit successful regeneration in the injured spinal cord. Future studies will focus on the neutralization of class 3 semaphorins, in order to reveal whether this creates a more permissive environment for regeneration of injured spinal cord axons.

Animals↗

PubMed2001

Perilymphatic application of cisplatin over several days in albino guinea pigs: dose-dependency of electrophysiological and morphological effects.

Cisplatin, at 0, 3, 30 or 300 microg/ml in saline, was applied to the scala tympani of the cochlea of guinea pigs via osmotic mini-pumps, operating at a pump rate of 0.5 microl/h. Electrocochleographic recordings were made from an implanted round window electrode. When an electrocochleographic criterion of ototoxicity was reached (40 dB loss in compound action potential (CAP) threshold at 8 kHz), or after 1 week if this criterion was not reached, the animals were sacrificed for light microscopy. A subgroup of animals had endocochlear potentials (EPs) measured prior to sacrifice. Hearing remained stable in the 0 microg/ml control group, but a sudden drop of auditory sensitivity across the whole frequency range was observed in all other groups. It took 1-5 days before the drop occurred, dependent on cisplatin concentration. CAP and cochlear microphonics were lost simultaneously. The EP was severely depressed in the affected animals, suggesting that cisplatin effects on the EP are primary. However, histology revealed an accompanying loss of outer hair cells, primarily in the basal turn. It is concluded that if cisplatin is given until ototoxicity becomes apparent electrophysiologically, then the cochlear pathology from intrascalar cisplatin administration resembles that from daily parenteral administration at 1.5-2.0 mg/kg. The cochlear pathology from the parenteral treatment was greater than that observed with 30 microg/ml pumps, and less than that from 300 microg/ml pumps.

Action Potentials↗

PubMed2001

Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state.

BACKGROUND: Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and alpha-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats. MATERIALS AND METHODS: Streptozotocin-diabetic rats were treated with different doses of alpha-lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser-Doppler flowmetry. RESULTS: We observed a rise in erythrocyte glutathione by 27 % (P < 0.05), and a trend towards decreased plasma malondialdehyde in alpha-lipoic acid, but not in glutathione-treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily alpha-lipoic acid administration by 38% (P < 0.05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment. CONCLUSIONS: Only minor beneficial effects of alpha-lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.

Animals↗

PubMed2001

Automated quantitative gait analysis during overground locomotion in the rat: its application to spinal cord contusion and transection injuries.

Analysis of locomotion is an important tool in the study of peripheral and central nervous system damage. Most locomotor scoring systems in rodents are based either upon open field locomotion assessment, for example, the BBB score or upon foot print analysis. The former yields a semiquantitative description of locomotion as a whole, whereas the latter generates quantitative data on several selected gait parameters. In this paper, we describe the use of a newly developed gait analysis method that allows easy quantitation of a large number of locomotion parameters during walkway crossing. We were able to extract data on interlimb coordination, swing duration, paw print areas (total over stance, and at 20-msec time resolution), stride length, and base of support: Similar data can not be gathered by any single previously described method. We compare changes in gait parameters induced by two different models of spinal cord injury in rats, transection of the dorsal half of the spinal cord and spinal cord contusion injury induced by the NYU or MASCIS device. Although we applied this method to rats with spinal cord injury, the usefulness of this method is not limited to rats or to the investigation of spinal cord injuries alone.

Abdomen↗

PubMed2001

Effects of enriched housing on functional recovery after spinal cord contusive injury in the adult rat.

To date, most research performed in the area of spinal cord injury focuses on treatments designed to either prevent spreading lesion (secondary injury) or to enhance outgrowth of long descending and ascending fiber tracts around or through the lesion. In the last decade, however, several authors have shown that it is possible to enhance locomotor function after spinal cord injury in both animals and patients using specific training paradigms. As a first step towards combining such training paradigms with pharmacotherapy, we evaluated recovery of function in adult rats sustaining a spinal cord contusion injury (MASCIS device, 12.5 mm at T8), either housed in an enriched environment or in standard cages (n = 15 in both groups). The animals in the enriched environment were stimulated to increase their locomotor activity by placing water and food on opposite sides of the cage. As extra stimuli, a running wheel and several other objects were added to the cage. We show that exposure to the enriched environment improves gross and fine locomotor recovery as measured by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, the BBB subscale, the Gridwalk, and the Thoracolumbar height test. However, no group differences were found on our electrophysiological parameters nor on the amount of spared white matter. These data justify further studies on enriched housing and more controlled exercise training, with their use as potential additive to pharmacological intervention.

Age Factors↗

PubMed2000

rhGGF2 protects against cisplatin-induced neuropathy in the rat.

In many patients treated with cisplatin a peripheral sensory neuropathy develops. This side-effect is considered dose-limiting, and therefore restricts the total dose of cisplatin that can be administered. Recent in vitro and in vivo studies suggest that recombinant human Glial Growth Factor 2 (rhGGF2) has neuroprotective effects. This prompted us to investigate in a rat model whether rhGGF2 ameliorates cisplatin neuropathy. A total of 48 rats were randomly divided into four groups of 12 rats each. Three groups received cisplatin and were treated with either 0.1 mg/kg rhGGF2, 0.3 mg/kg rhGGF2 or placebo. The fourth group (saline/placebo) served as age-matched controls. In the cisplatin/placebo treated rats a neuropathy developed, as determined by measurements of the nerve conduction velocity (NCV). Treatment with rhGGF2 dose-dependently protected against the neuropathy. Histological examination and morphometric analysis revealed that rhGGF2 also protects against cisplatin-induced changes in the morphology and size of DRG satellite cell nuclei. In a control study rhGGF2 did not affect normal NCV development. We conclude that rhGGF2 treatment is of benefit in the treatment of cisplatin neuropathy in the rat.

Animals↗

PubMed2000

Combined treatment with alphaMSH and methylprednisolone fails to improve functional recovery after spinal injury in the rat.

To date, relatively little progress has been made in the treatment of spinal cord injury (SCI)-related neurological impairments. Until now, methylprednisolone (MP) is the only agent with clinically proven beneficial effect on functional outcome after SCI. Although the mechanism of action is not completely clear, experimental data point to protection against membrane peroxidation and edema reduction. The melanocortin melanotropin is known to improve axonal regeneration following sciatic nerve injury, and to stimulate corticospinal outgrowth after partial spinal cord transection. Recently, we showed that intrathecally administered alphaMSH had beneficial effects on functional recovery after experimental SCI. Since both drugs have shown their value in intervention studies after (experimental) spinal cord injury (ESCI), we decided to study the effects of combined treatment. Our results again showed that alphaMSH enhances functional recovery after ESCI in the rat and that MP, although not affecting functional recovery adversely by itself, abolished the effects observed with alphaMSH when combined. Our data, thus, suggest that the mechanism of action of MP interferes with that of alphaMSH.

Action Potentials↗

PubMed2000

Pre- and postsynaptic localization of RC3/neurogranin in the adult rat spinal cord: an immunohistochemical study.

RC3 (neurogranin; BICKS) is a neuron-specific calmodulin-binding protein kinase C substrate. Thus far, immunohistochemical studies on the localization of RC3 revealed its presence in all neuronal phenotypes, which were restricted to specific areas in the neostriatum, the neocortex, and the hippocampus. RC3 was mostly found in cell bodies and dendrites, with some infrequent presence in axonal profiles, i.e. in the internal capsule. Until now, RC3 expression was reported to be absent in the adult rat spinal cord. RC3 might, however, act as an intermediate of protein kinase C-mediated signaling pathways during synaptic development and plasticity. We hypothesized a role for this 78-amino-acid protein in dendritic plasticity occurring after spinal cord injury. To our surprise, an immunohistological analysis of the uninjured adult rat spinal cord revealed the presence of RC3-positive cell bodies and dendrites in specific regions in the gray matter. Interestingly, axon-containing structures, such as the dorsal and ventral corticospinal tract, were also found to be RC3-positive. This axonal labeling was confirmed by preembedding electron microscopy. In conclusion, we demonstrate here that RC3 is present in the adult rat spinal cord in pre- and postsynaptic structures.

Animals↗

PubMed2000

Reversible cisplatin ototoxicity in the albino guinea pig.

Guinea pigs implanted with round window electrodes received daily doses (2.0 mg/kg) of cisplatin until a profound hearing loss occurred (> 40 dB at 8 kHz). Afterwards, pronounced recovery occurred. Recovery progressed over intervals up to 3 weeks before it saturated. Loss and recovery involved both the compound action potential and, less pronounced, the cochlear microphonics. Cochlear potentials evoked by lower frequencies recovered more fully than those evoked by higher frequencies. Loss and recovery was found also in the endocochlear potential. Outer hair cell counts did not change over the recovery period. These findings confirm our previously reported results on the reversibility of cisplatin damage. Further, they implicate the vascular stria as an important target for cisplatin in the cochlea.

Action Potentials↗

PubMed1999

Protection and spontaneous recovery from cisplatin-induced hearing loss.

Cisplatin [cis-diamminechloroplatinum(II)] has proved itself as a potent antineoplastic agent. However, nephrotoxicity, neurotoxicity, gastrointestinal toxicity, myelosuppression, and ototoxicity interfere with its therapeutical efficacy. Forced diuresis reduces nephrotoxicity, effectively leaving neurotoxicity and ototoxicity as the major side effects of concern, and gastrointestinal toxicity and myelosuppression as the secondary side effects. So far, attempts to reduce these side effects by developing equally potent platinum analogs have been unsuccessful. Some success has been achieved, however, by co-treatment with protective agents. Nearly all these agents are sulfur- or sulfhydryl-containing compounds (thio compounds), known as antioxidants and potent heavy metal chelators. These thio compounds may provide protection from cisplatin toxicity either (1) by direct interaction between the cisplatin and the thio moiety, (2) by displacing platinum from its site of toxic action, (3) by preventing platinum from interfering with superoxide dismutase, or (4) by scavenging of cisplatin-induced free radicals. In particular the first two protective mechanisms bear the risk of reducing the antineoplastic activity of cisplatin. Since nephrotoxicity can be controlled effectively by forced diuresis, a more specific approach of coping with ototoxicity by focusing on protection at the sensorineural level was chosen. Being familiar with the neuro-protective and neurotrophic properties of ACTH-related neuropeptides, specifically against cisplatin-induced peripheral neuropathies, it was judged expedient to test for a possible otoprotective action of these neuropeptides. The results were positive, although tainted with high interanimal variability. When testing for the possibility that the neuropeptides would merely delay cisplatin-induced ototoxicity rather than reduce it, it was discovered in control series without neuropeptide co-treatment that the ear can recover spontaneously from cisplatin-induced hearing loss. This was found both electrophysiologically and in outer hair cell (OHC) counts. Although these preliminary findings require further investigation, they strongly suggest that spontaneous recovery of cochlear injury can occur in the mature mammalian cochlea. Moreover, the otoprotective action of the ACTH-related neuropeptides suggests that it may be possible to stimulate recovery from acute hearing loss using neuropeptides.

Action Potentials↗

PubMed1999

Functional recovery after central infusion of alpha-melanocyte-stimulating hormone in rats with spinal cord contusion injury.

Melanocortins, peptides related to alpha-melanocortin-stimulating hormone (alpha MSH) and adrenocorticotropic hormone (ACTH), are known to improve axonal regeneration following peripheral nerve injury and stimulate neurite outgrowth from central nervous system (CNS) neurons both in vitro and in vivo. The neurite outgrowth promoting capacity of alpha MSH has prompted us to investigate the effects of intrathecal application of alpha MSH on functional and electrophysiological recovery in a well-characterized model of spinal cord contusion injury. Different doses of alpha MSH were applied via osmotic minipumps into the cisterna magna for 10 days, thereby delivering the peptide directly into the CNS. Functional recovery was monitored during 8 postoperative weeks by means of the Basso, Beattie, and Bresnahan locomotor rating scale, and the thoracolumbar height test. At the end of the study, electrophysiological analysis of rubrospinal motor evoked potentials as performed. Our data showed that application of 3.75 micrograms/kg/h alpha MSH resulted in a marked functional recovery, accompanied by a decrease in the latency of the rMEP. This study demonstrates that intrathecal application of alpha MSH results in functional recovery after spinal cord contusion injury. These findings may initiate new treatment strategies and/or the use of melanocortins in human spinal cord injury.

Analysis of Variance↗

PubMed1999

Neurophysiological changes in the central and peripheral nervous system of streptozotocin-diabetic rats. Course of development and effects of insulin treatment.

Diabetes mellitus can affect both the peripheral and the central nervous system. However, central deficits are documented less well than peripheral deficits. We therefore compared the course of development of neurophysiological changes in the central and peripheral nervous systems in streptozotocin-diabetic rats. Sciatic nerve conduction velocities and auditory and visual evoked potentials were measured prior to diabetes induction, and then monthly after diabetes induction for 6 months. In addition, the effect of insulin treatment was examined. Treatment was initiated after a diabetes duration of 6 months and was continued for 3 months. During treatment, evoked potentials and nerve conduction were measured monthly. In a third experiment, conduction velocities in ascending and descending pathways of the spinal cord were examined after 3 and 6 months of diabetes. Impairments of sciatic nerve conduction velocities developed fully during the first 2-3 months of diabetes. In contrast, increased latencies of auditory and visual evoked potentials developed only after 3-4 months of diabetes, and progressed gradually thereafter. Insulin treatment, initiated 6 months after induction of diabetes, improved both nerve conduction velocities and evoked potential latencies. Conduction velocities in the spinal cord tended to be reduced after 3 months of diabetes and were significantly reduced after 6 months of diabetes. The present study demonstrates that in streptozotocin-diabetic rats the course of development of peripheral and central neurophysiological changes differs. Peripheral impairments develop within weeks after diabetes induction, whereas central impairments take months to develop. Insulin can reverse both peripheral and central neurophysiological alterations.

Animals↗

PubMed1998

Local application of collagen containing brain-derived neurotrophic factor decreases the loss of function after spinal cord injury in the adult rat.

We studied the effect of local application of brain-derived neurotrophic factor (BDNF) on functional recovery after dorsal spinal cord transection in the adult rat. BDNF was applied at the site of the lesion in rat tail collagen type I. Locomotion was measured for 4 weeks using the BBB locomotor rating scale. One day after injury and application of BDNF the performance of treated rats was significantly increased as compared to controls (BBB-score 11.5+/-1.3 (mean +/- SEM) and 7.5+/-1.3, respectively). This difference remained significant during the first week. Histological examination of the spared spinal cord tissue at the lesion centre 4 weeks after lesioning showed no significant difference between control and BDNF-treated animals. The results indicate that local application of BDNF results in a decreased loss of function in the partially transected rat spinal cord starting one day after injury.

Animals↗

PubMed1997

Exercise training improves functional recovery and motor nerve conduction velocity after sciatic nerve crush lesion in the rat.

OBJECTIVE: To observe the effects of exercise training on recuperation of sensorimotor function in the early phase of regeneration, and to monitor the long-term effects of exercise on electrophysiological aspects of the regenerating nerve. DESIGN: After sciatic nerve crush in 20 male Wistar rats, one random selected group was subjected to 24 days of exercise training, whereas the other group served as sedentary controls. INTERVENTIONS: Exercise training was induced for 24 days, starting the first postoperation day, by placing bottles of water at such a height that the exercising rats had to maximally erect on both hindpaws to drink. MAIN OUTCOME MEASURES: Recovery of motor and sensory function in the early phase was monitored by analysis of the free walking pattern and the foot reflex withdrawal test, respectively. Electrophysiological measurements on postoperation days 50, 75, 100, 125, and 150 were used to evaluate the late phase of recovery of nerve conduction velocity. RESULTS: During the early phase of the recovery period, exercise training enhanced functional recovery. The motor nerve conduction velocity (MNCV), as measured in the late phase of recovery, was significantly better in the trained group than in the control group (p < .01). CONCLUSIONS: We conclude that exercise training enhances the return of sensomotoric function in the early phase of recovery from peripheral nerve lesion. Furthermore, these results suggest that the beneficial effects of 24 days of exercise training after crush persist in the late phase of peripheral nerve recovery.

Animals↗

PubMed1997

Co-administration of the neurotrophic ACTH(4-9) analogue, ORG 2766, may reduce the cochleotoxic effects of cisplatin.

In this study the effect of the neurotrophic ACTH(4-9) analogue, ORG 2766, on cisplatin cochleotoxicity was investigated with both light- and transmission electron microscopy. Guinea pigs were treated with either cisplatin+ORG 2766 (n = 11) or cisplatin + physiological saline (n = 9). All animals treated with cisplatin + physiological saline showed complete loss of outer hair cells (OHC) and degeneration of the organ of Corti in the basal cochlear turns, while partial OHC loss was found in the middle and apical turns. The inner hair cells (IHC) and other cochlear tissues were not affected. Eight animals from the group treated with cisplatin + ORG 2766 demonstrated similar pathological changes, but to a lesser degree, especially in the middle turns. The three remaining animals demonstrated no cochlear alterations at all, light-microscopically, and only minor subcellular changes in the OHCs at the ultrastructural level. Electrophysiologically, these three animals showed normals compound action potential (CAP) amplitudes at stimulus frequencies from 0.5 to 16 kHz and normal cochlear microphonics (CM) in the frequency range from 0.5 to 8 kHz. The other animals treated with cisplatin + ORG 2766 showed a severe loss in their CAPs and CM, except for one showing intermediate loss. All animals from the group treated with cisplatin alone showed a severe loss in their CAPs and CM. Endolymphatic hydrops was present in all animals from the cisplatin- and the cisplatin + ORG 2766-treated groups. These data indicate that daily, concomitant administration of ORG 2766 may reduce OHC loss and subsequent degeneration of the organ of Corti in cisplatin-treated guinea pig cochleas.

Acoustic Stimulation↗

PubMed1997

Beneficial effects of the melanocortin alpha-melanocyte-stimulating hormone on clinical and neurophysiological recovery after experimental spinal cord injury.

OBJECTIVE: Melanocortins, peptides related to melanocyte-stimulating hormone (MSH) and corticotropin (ACTH), exhibit neurotrophic and neuroprotective activity in several established models of peripheral and central nervous system damage. The beneficial effects of melanocortins on functional recovery after experimental brain damage and central demyelinating diseases have prompted us to investigate alpha MSH treatment in a weight drop model of traumatic spinal cord injury in rats. METHODS: In two independent randomized blinded experiments, treatment with either alpha MSH (75 micrograms/kg of body weight administered subcutaneously every 48 h for 3 weeks after trauma) or single high-dose (30 mg/kg, 30 min after injury) methylprednisolone was compared with saline treatment in rats subjected to a moderately severe 20-gcm weight drop injury. Spinal cord function was monitored using behavioral, electrophysiological, and histological parameters. RESULTS: In both experiments, alpha MSH significantly improved recovery, as illustrated by Tarlov scores, thoracolumbar height, and amplitude of rubrospinal motor evoked potentials. The magnitude of the alpha MSH effect on motor performance was comparable with the one observed after treatment with methylprednisolone. CONCLUSION: The reproducible neurological and electrophysiological improvement in spinal cord function of animals treated with alpha MSH suggests a new lead in the treatment of traumatic spinal cord injury.

Animals↗

PubMed1996

Upregulation of B50/GAP-43 protein mRNA in rat dorsal root ganglia during cisplatin intoxication.

Expression of the growth-associated protein B50 (GAP-43) mRNA in dorsal root ganglia (DRG) of rats was studied by in situ hybridization. In response to treatment with the neurotoxic agent cisplatin, B50 mRNA expression was significantly enhanced following a cumulative cisplatin dose of 14 mg/kg. In the untreated age-matched control animals, only half of the ganglion cells exhibited expression of B50 mRNA (mean hybridization signal, 10 times background), whereas at a cumulative cisplatin dose of 14 mg cisplatin every neuron exhibited well above background expression (mean hybridization signal, 34 times background). Cotreatment with a neuroprotective ACTH4-9 analog known to prevent cisplatin neuropathy in rats did not affect the overall expression of B50 mRNA. However, in the subpopulation of large sensory neurons, B50 mRNA content was significantly higher in the group cotreated with the ACTH4-9 analog as compared with the saline-cotreated group after 14 mg/kg of cisplatin. We conclude that in analogy with the well-known upregulation of B50 mRNA following mechanical nerve lesions, treatment with the neurotoxic drug cisplatin also leads to an increase in B50 mRNA expression. This observation lends strength to the hypothesis that in neuropathies an imbalance between regenerative and degenerative mechanisms exists. The ability of the larger sensory neurons to retain an increased B50 mRNA expression better after cotreatment with the peptide than without may be related to stimulation of regenerative processes by this ACTH4-9 analog.

Adrenocorticotropic Hormone↗

PubMed1996

New assessment techniques for evaluation of posttraumatic spinal cord function in the rat.

To evaluate new pharmacologic agents with potentially beneficial effects on posttraumatic spinal cord function, we used a modified weight drop (WD) technique to induce spinal cord injuries. These contusive spinal cord injuries in the rat closely mimic the human clinicopathologic situation. Especially for drug screening purposes, the moderate and mild injuries are of interest, as both the beneficial and potentially harmful effects of experimental treatment can be detected. In this study, we describe two new functional tests that were particularly designed to detect small differences in spinal cord function after moderate and mild injuries. First, for examination of locomotion, a computer analysis of the thoracolumbar height (TLH) was designed. Second, for investigation of the conduction properties of the injured rat spinal cord, we measured rubrospinal motor evoked potentials (MEP). The efficacy of the new assessment techniques to monitor spinal cord function was compared to Tarlov scores and to morphometric analysis of preserved white matter at the injury site. The results of this study indicated that for behavioral analysis, TLH measurements as compared with Tarlov rating appeared to be more sensitive for exact and objective discrimination between small differences in motor function. Amplitudes of the rubrospinal MEP, but not latencies or the number of peaks, proved to be most sensitive to determine subtle differences in posttraumatic spinal cord function. A significant linear correlation was found between TLH and amplitude of the rubrospinal MEP. We conclude that for objective assessment of the spinal cord after moderate and mild contusive injury, TLH and rubrospinal MEP amplitudes are very valuable measures to demonstrate small functional differences.

Animals↗