Biomedical subjects

Paul F Smith

Publications and source records attributed to Paul F Smith.

At least 55 records · Page 3Linked to original sources

PubMed2003

Cannabinoid CB1 receptor protein expression in the rat hippocampus and entorhinal, perirhinal, postrhinal and temporal cortices: regional variations and age-related changes.

Cannabinoids have been shown to disrupt memory processes and these effects occur primarily through cannabinoid CB1 receptors in the brain. The present study investigates, for the first time, the regional variations and age-related changes in CB1 protein expression in the hippocampus and its neighbouring entorhinal, perirhinal, postrhinal and temporal cortices using Western blotting. In young adult rats, CB1 protein was highly expressed in the hippocampus and within the hippocampus, the greatest density of CB1 protein was located in CA1. When a comparison was made between young (4-month-old) and aged (24-month-old) rats, CB1 protein expression was significantly increased in the aged entorhinal and temporal cortices and was significantly decreased in the aged postrhinal cortex. The present study demonstrates region-specific changes in CB1 protein expression during ageing and further suggests that cannabinoid CB1 receptors may contribute to the aging process.

Aging↗

PubMed2003

Long-term effects of permanent vestibular lesions on hippocampal spatial firing.

The hippocampus is thought to be important for spatial representation processes that depend on the integration of both self-movement and allocentric cues. The vestibular system is a particularly important source of self-movement information that may contribute to this spatial representation. To test the hypothesis that the vestibular system provides self-movement information to the hippocampus, rats were given either a bilateral labyrinthectomy (n = 6) or a sham surgery (n = 6), and at least 60 d after surgery hippocampal CA1 neurons were recorded extracellularly while the animals foraged freely in an open arena. Recorded cells were classified as complex spiking (n = 80) or noncomplex spiking (n = 33) neurons, and their spatial firing fields (place fields) were examined. The most striking effect of the lesion was that it appeared to completely abolish location-related firing. The results of this and previous studies provide converging evidence demonstrating that vestibular information is processed by the hippocampus. The disruption of the vestibular input to the hippocampus may interfere with the reconciliation of internal self-movement signals with the changes to the external sensory inputs that occur as a result of that movement. This would disrupt the ability of the animal to integrate allocentric and egocentric information into a coherent representation of space.

Analysis of Variance↗

PubMed2003

Nitric oxide synthase and arginase expression in the vestibular nucleus and hippocampus following unilateral vestibular deafferentation in the rat.

The aim of this study was to investigate the possible relationship between changes in neuronal and endothelial nitric oxide synthase (nNOS and eNOS) and arginase expression in the vestibular nucleus complex and the hippocampus (CA1, CA2/3 and the dentate gyrus (DG) at 10 h or 2 weeks following a unilateral vestibular deafferentation (UVD) in rats. There were no significant differences in nNOS or arginase II expression in the ipsilateral or contralateral VNC at either 10 h or 2 weeks post-UVD. For eNOS, there was only a significant decrease in expression in the ipsilateral VNC at 2 weeks post-UVD (P<0.01). In the hippocampus, the only significant difference in nNOS expression was a decrease in the ipsilateral DG at 2 weeks post-UVD (P<0.05). There was a significant decrease in eNOS expression in the contralateral CA2/3 region at 10 h post-UVD (P<0.01). The only other significant change in eNOS was an increase in the contralateral DG at 10 h post-UVD (P<0.01). Although arginase II was expressed in all regions of the hippocampus, there were no significant differences in arginase II expression at any time point following UVD. These results suggest that the changes in NOS expression that occur in the VNC and hippocampus following UVD are not correlated with one another or with changes in arginase II.

Animals↗

PubMed2003

Activation of the hypothalamic-pituitary-adrenal axis following vestibular deafferentation in pigmented guinea pig.

Twelve male pigmented guinea pigs underwent either a unilateral vestibular deafferentation (UVD) (n=6) or sham operation (n=6). Compared to the pre-operated salivary cortisol concentrations, the UVD operation resulted in a significant increase in night cortisol concentrations (P<0.05) and a significant interaction between the night cortisol concentration and time (P<0.05). There was no significant difference between the pre- and post-UVD morning salivary cortisol concentrations; nor between the pre- and post-sham morning or night salivary cortisol concentrations. This study suggests that the ocular-motor and postural syndrome is causing the activation of the hypothalamic-pituitary-adrenal (HPA) axis.

Animals↗

PubMed2003

Adrenalectomy-induced cell death in the dentate gyrus: further characterisation using TUNEL and effects of the Ginkgo biloba extract, EGb 761, and ginkgolide B.

This study investigated the potential neuroprotective effects of the Ginkgo biloba extract, EGb-761, and ginkgolide B, on adrenalectomy (ADX)-induced cell death in the dentate gyrus (DG). Adrenalectomised, sham surgery-treated, and naive controls received either EGb-761 (25, 50, or 100 mg/kg), 0.9% saline vehicle control, ginkgolide B (10 or 25 mg/kg), or a polyethylene glycol vehicle control, i.p, daily for 6 days postsurgery. Cell death in the DG was determined by in situ labelling of DNA fragments, using the TUNEL method; sections were counterstained with hematoxylin. Radioimmunoassay was used to confirm a decrease in plasma corticosterone (CORT) after ADX. TUNEL-positive granule cells were observed in the DG at 1 week, but not at 24 h, post-ADX. The rate of granule cell death at this time was highest in the suprapyramidal blade and increased in a crest tip and a rostrotemporal gradient. Whereas CORT replacement completely prevented the occurrence of TUNEL-positive granule cells, EGb-761 and ginkgolide B did not, at any of the doses used. These results suggest that these drugs may not have substantial neuroprotective effects in the ADX model of neurodegeneration.

Adrenalectomy↗

PubMed2003

Changes in NOS protein expression and activity in the rat hippocampus, entorhinal and postrhinal cortices after unilateral electrolytic perirhinal cortex lesions.

The integrity of the perirhinal cortex is critical for certain types of learning and memory. One important issue relating to the function of this region is its interaction with other brain areas that play a role in memory processing. This study investigates the time course of changes in activity and protein expression of nitric oxide synthase (NOS), which transforms L-arginine into nitric oxide (NO) and citrulline, in the hippocampus and the entorhinal and postrhinal cortices after unilateral electrolytic lesions of the perirhinal cortex. Electrolytic lesions of the perirhinal cortex resulted in long lasting changes in NOS activity and protein expression in the entorhinal and postrhinal cortices (< or = 2 weeks post-lesion). In contrast, there was a small and transient decrease in nNOS expression (with no change in NOS activity) in the dorsal portion of the hippocampus. iNOS was not expressed in any region examined at any time point. These findings provide the first evidence that electrolytic lesions of the perirhinal cortex can result in long-term neurochemical changes in its anatomically related structures. Given that NO has been implicated in neuroplasticity processes, the interpretation of memory impairments induced by electrolytic lesions of the perirhinal cortex (and possibly, therefore, other brain regions) need to be considered with regard to these findings.

Animals↗

PubMed2003

Nitric oxide synthase and arginase in the rat hippocampus and the entorhinal, perirhinal, postrhinal, and temporal cortices: regional variations and age-related changes.

Increasing evidence suggests that nitric oxide synthase (NOS)/nitric oxide (NO) contributes to the aging process. By contrast, the role of arginase, which shares a common substrate with NOS, has not been determined. In the present study, regional variations and age-related changes in NOS and arginase in the hippocampus and its neighboring structures were investigated for the first time. In young adult rats, high levels of NOS activity were found in the entorhinal, perirhinal, and postrhinal cortices, whereas low values were located in the hippocampus and the temporal cortex. Interestingly, arginase activity showed an overall inverse pattern with the lowest levels in the entorhinal and perirhinal cortices. When a comparison was carried out between young (4-month-old) and aged (24-month-old) rats, significant increases in total NOS activity were found in the aged entorhinal and temporal cortices, and a significant decrease in arginase activity was observed in the aged postrhinal cortex. Western blotting demonstrated significant decreases in both neuronal and endothelial NOS expression in the aged hippocampus and postrhinal cortex, whereas arginase I and II expression did not show age-related changes in any region examined. Activity and protein expression of inducible NOS were not detected in any tissue from either group. The present findings of region-specific changes in NOS and arginase appear to support the potential involvement of NOS/NO in the aging process and raise the issue of a possible contribution of arginase to aging.

Aging↗

PubMed2003

Unilateral inner ear damage results in lasting changes in hippocampal CA1 field potentials in vitro.

We investigated the effects of a surgical lesion of one vestibular inner ear (unilateral vestibular damage [UVD]) on the field potential responses of CA1 neurons in vitro. Hippocampal slices were removed from rats at 4-6 weeks or 5-6 months post-UVD, and the field responses of CA1 neurons to electrical stimulation of the Schaffer collateral commissural pathway were analyzed. Compared with slices from sham and naive control animals, slices from UVD animals at 5-6 months post-UVD exhibited decreases in the population spike amplitude, the somal field excitatory postsynaptic potential (sfEPSP) slope, and the field EPSP (fEPSP) slope. For the population spike amplitude and fEPSP slope, this effect was observed in both CA1 ipsilateral and contralateral to the UVD. On both the ipsilateral and contralateral sides, paired-pulse testing showed increases in paired-pulse inhibition at the shortest interstimulus intervals (ISIs), with increases in paired-pulse facilitation at longer ISIs. This study provides the first evidence that peripheral vestibular damage can produce long-term changes in hippocampal electrophysiological activity in vitro.

Action Potentials↗

PubMed2003

Interaction between the hypothalamic-pituitary-adrenal axis and behavioural compensation following unilateral vestibular deafferentation.

Vestibular compensation is defined as the process of behavioural recovery that occurs following the loss of sensory input from one or both vestibular labyrinths. The visual and postural instability resulting from the vestibular damage must alter the homeostasis of the subject; however, very little research has been conducted that investigates the interaction between vestibular compensation and the adaptive stress response of the body, i.e. the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this review is to describe and evaluate the experimental evidence indicating a link between vestibular compensation and the body's response to stress, via the HPA axis.

Animals↗

PubMed2003

Effect of low body temperature during unilateral labyrinthectomy on vestibular compensation in the guinea pig.

OBJECTIVES: Vestibular compensation, the recovery that follows unilateral vestibular deafferentation (UVD), is a model for central nervous system plasticity. Recovery from the static symptoms of UVD may involve temperature-dependent processes that modulate the immediate effects of UVD and/or the capability of the central nervous system to undergo adaptive plasticity. In this study we investigated changes in oculomotor and postural vestibular symptoms resulting from low body temperature during UVD. MATERIAL AND METHODS: To study the effect of low temperatures at the time of UVD on vestibular compensation, we compared the rate of compensation and peak values for postural [roll head tilt (RHT) and yaw head tilt (YHT)] and oculomotor [spontaneous nystagmus (SN)] symptoms in three groups of guinea pigs. Animals in Group 1 (n = 6) were maintained at 38 degrees C throughout unilateral labyrinthectomy (UL). Animals in Group 2 (n = 6) were not temperature-controlled and animals in Group 3 (n = 4) were cooled with ice to 25 degrees C throughout UL. RESULTS: Cooled animals showed significantly higher rates of SN upon recovery from anaesthesia and took a significantly longer time to compensate. Cooled animals were also slower to compensate for postural symptoms (RHT and YHT), with 2 animals showing no compensation for RHT 52 h after UL. CONCLUSION: Hypothermia (25 degrees C) during UVD surgery exacerbates postural and oculomotor symptoms following UL and significantly slows recovery.

Animals↗

PubMed2003

Therapeutic N-methyl-D-aspartate receptor antagonists: will reality meet expectation?

The initial promise of the N-methyl-D-aspartate (NMDA) receptor antagonists gave hope for the therapeutic treatment of neurological disorders, which ultimately was unfulfilled. In many cases, their adverse psychotomimetic effects were too severe for them to be used therapeutically in the way that most had envisaged. The last decade has seen significant progress in our understanding of the NMDA receptor complex and the site(s) of action of various uncompetitive antagonists. In particular, this has led to the development of a family of low-affinity, uncompetitive, cation channel antagonists that seem to offer many of the benefits of the older channel blockers but with a more acceptable side effect profile. Drugs such as memantine have demonstrated beneficial effects in clinical trials for Alzheimer's disease and ischemia, with few adverse side effects. Likewise, the NMDA receptor NR2B subunit antagonists derived from drugs such as ifenprodil, have proven beneficial in the treatment of neuropathic pain, and are also associated with few adverse side effects. These, and other new experimental agents, are demonstrating that it may yet be possible to tap the enormous potential of NMDA receptor antagonists as therapeutic drugs, without necessarily incurring the adverse side effects associated with the first generation compounds.

Animals↗

PubMed2003

Vestibulotoxicity following aminoglycoside antibiotics and its prevention.

It has been assumed that aminoglycoside-induced damage to the vestibular inner ear ('vestibulotoxicity') is solely due to the inhibition of mitochondrial protein synthesis. There is now substantial evidence, however, to suggest that this form of neurotoxicity is due, at least in part, to the production of free radicals; either in response to excessive stimulation of the N-methyl-D-aspartate (NMDA) receptor by aminoglycosides, or from the formation of oxidative compounds following the binding of aminoglycosides to iron. If activation of NMDA receptors by aminoglycosides contributes to this hair cell death, it should be possible to modify the chemical structures of the aminoglycosides in ways that minimize the unwanted action. Researchers are also currently evaluating drugs that could be co-administered with aminoglycosides in order to interfere with the apoptotic cascade. For example, NMDA receptor antagonists, nitric oxide synthase inhibitors, caspase inhibitors, neurotrophins and free radical scavengers have been demonstrated to protect against aminoglycoside-induced vestibulotoxicity in experimental studies. The next step will be to pursue these effects using in vivo models and drugs that are likely to have favorable pharmacokinetic and side effect profiles in humans.

Aminoglycosides↗

PubMed2003

Bilateral peripheral vestibular lesions produce long-term changes in spatial learning in the rat.

In order to investigate whether bilateral peripheral vestibular lesions cause long-term impairment of spatial learning, rats were tested in a reference memory radial arm maze learning task at least 5 weeks following a bilateral labyrinthectomy (BL) or sham control lesion. All control rats reached criterion (i.e., 1 error or less, averaged across 7 trials for 3 consecutive days of training) but only 4 of the 8 BL rats had reached criterion by day 21 of the training sessions. The control rats reached criterion more quickly than the lesioned rats (Control, 7.0 +/- 0.63 days, Lesioned, 15.8 +/- 1.4 days, t10= 5.84, p < 0.0001). This difference resulted from the greater number of errors made by the BL animals. However, the latency to respond was comparable as a result of the increased locomotor activity of the BL group (i.e., 'hyperkinesis), and the overall rate of acquisition of the task, as indicated by analysis of the exponential decrease in errors over the entire training period, was not significantly different between the 2 groups. The results of this study demonstrate that BL in rats produces long-term changes in performance in a spatial reference memory task, which are not simply due to the inability to move but may relate to the way that the brain uses vestibular information to create spatial representations and determines behavioural strategies on the basis of these representations.

Animals↗

PubMed2003

Neuroprotection against hypoxia-ischemia by insulin-like growth factor-I (IGF-I).

Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has been investigated as a potential neuroprotective drug for the treatment of stroke and other forms of neural damage. Preclinical studies over the last decade have demonstrated that IGF-I and some of its fragments can protect against neuronal and glial cell degeneration in animal models of stroke such as hypoxia-ischemia. Although the results to date are encouraging, the size of the IGF-I molecule has proved problematic and has led researchers to investigate routes of administration that bypass the blood-brain barrier, such as intranasal application, or to focus on fragments of IGF-I, such as the N-terminal peptide Gly-Pro-Glut (GPE). While the results of these studies have also been positive, systematic dose-response comparisons with recognized neuroprotectants have not yet been published, the time window for therapeutic effects is not yet clear and long-term functional studies have not been conducted.

Animals↗

PubMed2002

NMDA and AMPA receptor subunit protein expression in the rat vestibular nucleus following unilateral labyrinthectomy.

We examined the expression of the NR1 and NR2A subunits of the N-methyl-D-aspartate (NMDA) receptor, and the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor, in the ipsilateral and contralateral vestibular nucleus complexes (VNCs) at 10 h and 2 weeks following unilateral vestibular deafferentation (UVD) in rats, in order to directly test the hypothesis that the behavioural recovery following UVD ('vestibular compensation') is associated with an up-regulation of NMDA receptors. We found no significant changes in NR1 or NR2A expression at 10 hs or 2 weeks post-op. compared to sham and anesthetic controls. We did find a significant (p < 0.01 and p < 0.05) increase in GluR2 expression in both VNCs at 10 h but not 2 weeks post-op. compared to sham and anesthetic controls; however, comparison over time post-UVD failed to detect a significant difference, suggesting that it was small and transient at best. These results add further evidence to the conclusion that NMDA receptors do not undergo up-regulation in the ipsilateral VNC during vestibular compensation.

Animals↗

PubMed2002

Vestibulo-ocular, optokinetic and postural function in humans with rheumatoid arthritis.

The present study investigated vestibulo-ocular reflex (VOR), optokinetic reflex (OKR) and postural function in patients with rheumatoid arthritis (RA). Compared with controls, no differences in gaze-holding, VOR gain or phase, OKR slow phase velocity (SPV) or quick phase amplitude, optokinetic afternystagmus SPV or duration, or latency to the illusion of circularvection, were found. RA patients did exhibit greater sway in the leftward direction (P<0.01), however, this was no greater in the conditions of the Clinical Test of Sensory Interaction and Balance that increase reliance upon vestibular information. We conclude that RA patients do not exhibit substantial deficits in visual-vestibular function.

Aged↗

PubMed2002

Vestibulo-ocular, optokinetic and postural function in diabetes mellitus.

We compared vestibulo-ocular reflex, optokinetic reflex and postural function in subjects with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), as well as non-diabetic controls. Both IDDM and NIDDM subjects exhibited significant deficits in gaze-holding in darkness (p < 0.05), small changes in vestibulo-ocular reflex (VOR) phase re velocity (p < 0.005) without a change in VOR gain, and a decrease in optokinetic reflex (OKR) slow phase velocity (p < 0.001). In addition, a smaller decrease was found in OKR quick phase amplitude (p < 0.02); postural sway was increased in both diabetic groups (p < 0.05), although this was not specific to the conditions of the Clinical Test of Sensory Interaction and Balance (CTSIB) that test vestibular contributions to postural stability. No differences were found in optokinetic afternystagmus or latency to circularvection. These results suggest that both IDDM and NIDDM are associated with deficits in gaze-holding, VOR and OKR function.

Adult↗

PubMed2002

The CNS effects of Ginkgo biloba extracts and ginkgolide B.

Ginkgo biloba extracts such as EGb-761 have been suggested to have a multitude of beneficial effects on CNS function, from enhancing cognitive function in dementia to facilitating recovery from acute forms of neural damage such as hypoxia/ischemia. Ginkgolide B, one of the major components of EGb-761, is a potent platelet-activating factor (PAF) receptor antagonist, which is also regarded as having neuroprotective effects in the CNS. The aim of this review is to summarise and to critically evaluate the current evidence on the CNS effects of EGb-761 and ginkgolide B, with particular emphasis on the data relating to their neuroprotective effects.

Brain↗