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Biomedical subjects

Paul F Smith

Publications and source records attributed to Paul F Smith.

At least 37 records · Page 2Linked to original sources

The safety of cannabinoids for the treatment of multiple sclerosis.

The evidence for the therapeutic efficacy of cannabinoids in the treatment of multiple sclerosis (MS) is increasing but is not as yet convincing. Although several trials have reported no significant effect, the majority of the evidence which supports a beneficial effect on spasticity and pain is based on subjective measurements in trials where unblinding was likely to be a problem. The available clinical trial data suggest that the adverse side effects associated with using cannabis-based medicinal extracts (CBMEs) are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication, and in no case did toxicity develop. However, most of these trials were run over a period of months and it is possible that other adverse side effects, not seen in these short-term studies, could develop with long-term use. Despite the evidence that cannabinoids can disrupt cognitive function and promote depression, on the basis of current data, such adverse effects seem unlikely to be associated with the use of CBMEs. Likewise, there is no evidence to suggest that their effects on balance and motor control, or immune function, may be clinically significant. There is, however, reason to be concerned about the use of therapeutic cannabinoids by people predisposed to psychosis and by pregnant women, given the increasing evidence of their adverse effects on the fetus. In conclusion, given the modest therapeutic effects of cannabinoids demonstrated so far, and the risk of long-term adverse side effects, there is reason to be cautious about their use in the treatment of MS.

Adult↗

Does vestibular damage cause cognitive dysfunction in humans?

For more than a decade, evidence from animal studies has suggested that damage to the vestibular system leads to deficits in spatial navigation which are indicative of impaired spatial learning and memory. More recently, direct evidence has emerged to demonstrate that humans with vestibular disorders exhibit a range of cognitive deficits that are not just spatial in nature, but also include non-spatial functions such as object recognition memory. Vestibular dysfunction has been shown to adversely affect attentional processes and increased attentional demands can worsen the postural sway associated with vestibular disorders. Recent MRI studies also show that humans with bilateral vestibular damage undergo atrophy of the hippocampus which correlates with their degree of impairment on spatial memory tasks. These results are consistent with those from animal studies and, together, suggest that humans with vestibular disorders are likely to experience cognitive dysfunction which is not necessarily related to any particular episode of vertigo or dizziness, and therefore may occur even in patients who are otherwise well compensated. These findings may be related to the observation that patients with vestibular deficits experience a high incidence of depression and anxiety disorders.

Animals↗

Cannabinoids as potential anti-epileptic drugs.

Cannabinoids have long been recognized as having the potential for both anticonvulsant and proconvulsant effects. The increased understanding of the cannabinoid receptors and their endogenous ligands over the last decade has provided a potential mechanism of action for these apparently paradoxical effects. Although the anticonvulsant effects of cannabinoids appear to be mediated by their action at presynaptic cannabinoid receptors, which inhibit the release of excitatory neurotransmitters such as glutamate, it is clear that they are also capable of producing proconvulsant effects through the activation of cannabinoid receptors on terminals releasing inhibitory neurotransmitters, such as gamma-amino-butyric acid. In the brain, the activation of cannabinoid receptors is carefully controlled by the rapid synthesis and degradation of endocannabinoids in a way that targets the endogenous ligands to specific sets of cannabinoid receptors. The potential problem in delivering a cannabinoid drug to treat epilepsy is the inability to control its actions at different cannabinoid receptors regulating the release of different neurotransmitters. Since the action of cannabinoids is complex, and there is a dearth of clinical trial data, it is currently unclear whether cannabinoids might be both efficacious and safe in the treatment of epilepsy.

Animals↗

Drug treatments for subjective tinnitus: serendipitous discovery versus rational drug design.

Progress has been made in understanding the neural basis of subjective tinnitus (ST); however, this has not, as yet, translated into many new drug treatments. One reason for this is that realistic behavioral models of ST in animals have been developed only recently, and are still not widely used. Nonetheless, some significant pharmacological advances have been made. At present, there is evidence to support the efficacy of transtympanic gentamicin administration in the treatment of tinnitus associated with Meniere's disease; there is also some evidence to support the efficacy of intratympanic steroid and lidocaine application in the management of ST. Although benzodiazepines and anti-epileptic drugs appear to be effective in many cases of this condition, there is concern about their adverse side effect profile. Based on well-controlled clinical trials, vasodilators such as misoprostol, and histamine receptor ligands should be further investigated. Finally, given the evidence that ST is a form of sensory epilepsy, new antiepileptic drugs should be tested for potential efficacy as they are developed; such drugs may include novel N-methyl-D-aspartate receptor antagonists, as well as cannabinoids.

Anticonvulsants↗

Immunocytochemical and stereological studies of the rat vestibular nucleus: optimal research methods using glucocorticoid receptors as an example.

Many anatomists agree that stereological procedures for counting neurons are superior to simple density measurements because the latter are biased by the way that sections are sampled and the likelihood of selectively sampling neurons of particular sizes and orientations. Despite this, few stereological studies of the vestibular nucleus complex (VNC) have been conducted and all of the published immunocytochemical studies have used densitometry to quantify receptor numbers. One possible reason for this is the difficulty of combining stereological methods with immunocytochemical techniques required to label specific types of receptors. In this paper we detail the optimal methods for combining stereological and immunocytochemical techniques for the unbiased quantification of neuronal number, using glucocorticoid receptors as an example. We report that the cryofixation method is more effective than perfusion with paraformaldehyde, in order to obtain sections to estimate neuronal number using the Cavalieri and physical disector methods. Thionin proved to be the optimal counterstain for identifying both neurons and the boundaries of the VNC. The combination of stereological and immunocytochemical techniques offers an effective means to ensure accurate estimates of the number of neurons expressing a receptor.

Animals↗

Cytosolic glucocorticoid receptor expression in the rat vestibular nucleus and hippocampus following unilateral vestibular deafferentation.

It has been suggested that vestibular compensation, the process of behavioural recovery that occurs following peripheral vestibular damage, might be partially dependent on the release of glucocorticoids (GC) during the early stages of recovery from the lesion. One possibility is that glucocorticoid receptors (GRs) in the vestibular nucleus complex (VNC) might change following the lesion, altering their response to GCs. We sought to test this hypothesis by quantifying the expression of cytosolic GRs in the bilateral VNCs at 10 h, 58 h and 2 weeks following unilateral vestibular deafferentation (UVD) in rat, using western blotting. We also examined GR expression in the CA1, CA2/3 and dentate gyrus (DG) subregions of the hippocampus and measured serum corticosterone levels. Compared with sham surgery and anaesthetic controls, we found no significant changes in GR expression in the ipsilateral or contralateral VNCs at any time post-UVD. However, we did find a significant decrease in GR expression in the ipsilateral CA1 at 2 weeks post-UVD. Serum corticosterone levels were significantly lower in all groups at 58 h post-op. compared to 10 h and 2 weeks; however, there were no significant differences between the UVD and control groups at any time point. These results suggest that changes in GR expression in the VNC are unlikely to contribute to the development of vestibular compensation. However, long-term changes in GR expression in CA1 might be related to chronic deficits in hippocampal function and spatial cognition following vestibular damage.

Adaptation, Physiological↗

Rapid vestibular compensation in guinea pig even with prolonged anesthesia.

The results of previous studies have suggested that prolonged anesthesia following unilateral labyrinthectomy (UL) results in a retardation of vestibular compensation, the process of behavioral recovery that occurs following the lesion. In this study we investigated the effects of short-term (25 min) and long-term (4 h) anesthesia with isoflurane on the time course of vestibular compensation following UL in guinea pig. Although there were significant differences in the frequency of spontaneous nystagmus (SN) (p < 0.05) and its rate of compensation (p < 0.05) between the 25 min and 4h isoflurane groups, these differences appeared to be due largely to the 5, 9 and 13 h time points. There was also a significant difference in the rate of yaw head tilt (YHT) compensation, largely due to the 5 h time point. When exponential regression analysis was performed to evaluate the overall pattern of compensation, there was no significant difference in the time required to reach 100% SN or YHT compensation between the 25 min and 4 h isoflurane groups. Furthermore, there were no significant differences in roll head tilt (RHT) compensation between the two groups. These results suggest that the time course of vestibular compensation is largely independent of the duration of the anesthesia used for UL surgery.

Anesthesia↗

Immunohistochemical characterisation and localisation of cannabinoid CB1 receptor protein in the rat vestibular nucleus complex and the effects of unilateral vestibular deafferentation.

CB1 receptor expression has been reported to be low in the brainstem compared with the forebrain, and low in the vestibular nucleus complex (VNC) compared with other regions in the brainstem. However, a frequent effect of cannabis is dizziness and loss of balance. This may be due to the activation of cannabinoid receptors in the central vestibular pathways. We used immunohistochemistry to study the distribution of CB1 receptor protein in the VNC, and Western blotting to measure CB1 receptor expression in the VNC following unilateral vestibular deafferentation (UVD); the hippocampal CA1, CA2/3 and dentate gyrus (DG) regions were also analysed for comparison. This study confirms a previous electrophysiological demonstration that CB1 receptors exist in significant densities in the VNC and are likely to contribute to the neurochemical control of the vestibular reflexes. Nonetheless, CB1 receptor expression did not change significantly in the VNC during vestibular compensation. In addition, despite some small but significant changes in CB1 receptor expression in the CA2/3 and the DG following UVD, in no case were these differences statistically significant in comparison to both control groups.

Animals↗

Bilateral labyrinthectomy causes long-term deficit in object recognition in rat.

It has been reported that patients with vestibular disorders experience a wide range of cognitive disorders, including memory loss. However, to our knowledge, no study has investigated the contribution of vestibular information to episodic memory in experimental animals using vestibular deafferentation. In the present study, the effects of a complete unilateral or bilateral surgical lesion of the vestibular labyrinths in a spontaneous object recognition task were evaluated in Wistar rats 3 and 6 months following the surgery. We found that rats with bilateral vestibular deafferentation, but not those with unilateral vestibular deafferentation were impaired on the task at both time points. These results suggest for the first time that vestibular information may contribute to non-spatial memory to some extent.

Analysis of Variance↗

Cannabinoid CB1 receptor protein expression in the rat choroid plexus: a possible involvement of cannabinoids in the regulation of cerebrospinal fluid.

Cannabinoid CB1 receptors in the brain are expressed on axon terminals presynaptic to neurons that express fatty acid amide hydrolase (FAAH). Postsynaptic FAAH catabolizes endocannabinoids which act as short-range transmitters. It has been previously shown that FAAH is also expressed in the epithelial cells of the choroid plexus. Using immunohistochemisty, we found that CB1 receptor protein is also expressed in choroid plexus epithelia. This is consistent with the hypothesis that FAAH in choroid plexus epithelial cells catabolizes endocannabinoids close to their site of action. Cannabinoids may then act directly on choroid plexus cells, and thereby contribute to the regulation of the composition of the CSF.

Animals↗

Immunohistochemical localization of cannabinoid CB1 receptor in inhibitory interneurons in the cerebellum.

Inhibitory interneurons terminating on Purkinje cell dendrites contribute to cannabinoid-mediated cerebellar plasticity, consistent with the intense expression of cannabinoid CB1 receptor protein in the cerebellar molecular layer. CB1 labelling in the molecular layer has been attributed to parallel fibers originating from granule cells, climbing fibers originating in the inferior olive, and inhibitory interneurons in the deep molecular layer (basket cells). However, the cellular distribution of CB1 in the cerebellar molecular layer has remained poorly understood. We used double fluorescence labelling to test for co-localization of nuclei with CB1 receptor protein. Labelling was intense surrounding nuclei in the deep and superficial molecular layer; consistent with basket cell and stellate cell inhibitory interneurons that regulate depolarization-induced suppression of inhibition (DSI) of Purkinje cells.

Animals↗

Immunohistochemical localization of cerebrovascular cannabinoid CB1 receptor protein.

Cannabinoids are powerful hypotensives and vasodilators. However, their mode of action is controversial. This study is the first to investigate the distribution of vascular CB1 receptor protein expression in situ. We used double-fluorescence and chromogenic immunohistochemistry to investigate patterns of CB1 protein expression in cerebrovascular tissue in rat brain sections. We found a layer of intense CB1 labeling immediately adjacent to the internal elastic lamina, consistent with myointimal and vascular smooth muscle cells, and diffuse labeling adventitial to this layer. We concluded that CB1 receptor are most intensely expressed in the vascular smooth muscle layer in cerebral arteries, and are likely to be chiefly responsible for the potent vasodilatory effect of cannabinoids.

3,3'-Diaminobenzidine↗

Microarray analysis of gene expression in the rat vestibular nucleus complex following unilateral vestibular deafferentation.

To investigate the molecular background of vestibular compensation, a model of lesion-induced plasticity, we used a microarray analysis to examine genes that show asymmetrical expression between the bilateral vestibular nucleus complexes (VNCs) 6 h following unilateral vestibular deafferentation (UVD). Asymmetrical gene expression was then validated by a real-time quantitative PCR. Among the 88 genes for which the ipsilateral (ipsi) : contralateral (contra) was > 1.35, the number of known genes was 33 (38%), and the number of expressed sequence tag (EST) sequences was 55 (62%). Among the 130 genes for which the contra : ipsi was > 1.35, the number of known genes was 55 (42%), and the number of EST sequences was 75 (58%). Changes in some of the genes were consistent with previous studies; however, we found several new genes which could be functionally related to the molecular basis of the electrophysiological asymmetry between the VNCs following UVD. Ipsi > contra genes included the GABA(A) receptor rho subunit, regulatory proteins of G protein signaling, calcium signaling related molecules such as the voltage-dependent calcium channel alpha2/delta subunit 1, calcineurin subunit Abeta and Ca(2+) pump. Contra > ipsi genes included the neuronal high affinity glutamate transporter, 5-hydroxytryptamine receptor 1D, mitogen-activated protein kinase 12 and ubiquitin carboxy-terminal hydrolase L1.

Animals↗

Medicinal cannabis extracts for the treatment of multiple sclerosis.

Prior to 2002, few clinical data were available to indicate whether cannabis extracts may be beneficial. However, in the last two years, results of several placebo-controlled clinical trials of orally administered compounds have been published, and these cast doubt on the efficacy of delta9-tetrahydrocannabinol (delta9-THC) in objectively reducing spasticity in MS. By contrast, it has been claimed that sublingually administered cannabis extracts that contain approximately equal concentrations of delta9-THC and cannabidiol, a natural cannabinoid that does not act on the CB1 receptor, can produce a statistically and clinically significant reduction in spasticity, although this claim has yet to be thoroughly validated. Nonetheless, results of preclinical trials also lend support to the hypothesis that the endogenous cannabinoid system may be involved in the regulation of spasticity and pain. A better indication of the clinical potential of the different cannabis extracts will have to await the publication of the most recent clinical trial data. This review critically evaluates the most recent evidence available on the potential use of medicinal extracts of cannabis to relieve pain and spasticity in multiple sclerosis.

Animals↗

GW-1000. GW Pharmaceuticals.

GW Pharmaceuticals is developing GW-1000 (Sativex), a narrow ratio delta9-tetrahydrocannabinol:cannabidiol product for the potential treatment of multiple sclerosis, spinal cord injury, neurogenic pain and peripheral neuropathy. In March 2003, the company filed for approval for the treatment of MS with the UK Medicines Control Agency, and in May 2004, filed for new drug submission with Health Canada.

Administration, Oral↗

Nitric oxide synthase and arginase expression changes in the rat perirhinal and entorhinal cortices following unilateral vestibular damage: a link to deficits in object recognition?

Previous studies have shown that peripheral vestibular damage causes long-term neurochemical changes in the hippocampus which may be related to spatial memory deficits. Since recent studies have also demonstrated deficits in non-spatial object recognition memory following vestibular lesions, the aim of the present study was to extend these investigations into the perirhinal cortex (PRC), which is known to be important for object recognition, and the related entorhinal cortex (EC). We examined the effects of unilateral vestibular deafferentation (UVD) on the expression of four enzymes associated with neuronal plasticity, neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), arginase I and arginase II (AI and II), in the rat EC and PRC using Western blotting. Tissue was collected at 10 hs, 50 hs and 2 weeks post-UVD. In the EC and PRC, nNOS protein expression decreased on the contralateral side at 2 weeks post-UVD but not before. At the same time, eNOS protein expression increased in both regions on the contralateral side. In the EC, AII protein expression increased on the ipsilateral side at 2 weeks post-UVD. In the PRC, AI increased and decreased on the contralateral and ipsilateral sides (respectively) at 2 weeks post-UVD. AII showed a bilateral increase in the PRC at 2 weeks post-UVD. These results demonstrate changes in NOS and arginase protein expression in the PRC and EC following UVD, which are unlikely to be due to the initial severity of the vestibular syndrome because they develop well after vestibular compensation has taken place. Neurochemical changes in these regions of the medial temporal lobe may be implicated in the development of object recognition deficits that contribute to cognitive dysfunction following peripheral vestibular damage.

Analysis of Variance↗

Effects of unilateral labyrinthectomy on GAD, GAT1 and GABA receptor gene expression in the rat vestibular nucleus.

To elucidate the role of the GABAergic neuronal system in the recovery from peripheral vestibular damage (unilateral labyrinthectomy), we used a real-time quantitative reverse transcription-polymerase chain reaction method to investigate the mRNA expression of GAD65, GAD67, the GABAA receptor alpha1 subunit, the GABAB R1 subunit, and the GABA transporter GAT1, in the vestibular nucleus complex of the rat 6 and 50 h following the lesion GAD65 and GAD67 gene expression were also measured in the flocculus. The GABAA alpha 1 subunit mRNA was up-regulated in the ipsilateral vestibular nucleus 6 h post-lesion but decreased in expression thereafter. GAD65 mRNA was up-regulated in the vestibular nuclei bilaterally 50 h after the lesion. In the flocculus, GAD65 mRNA expression was bilaterally up-regulated 50 h post-operatively. GAT1 mRNA expression was initially up-regulated in the ipsilateral vestibular nucleus and then underwent a bilateral increase 50 h post-operatively. These results demonstrate that following unilateral labyrinthectomy, major changes in the expression of GAD, GAT and GABA receptor subunit genes occur in the vestibular nucleus, which are likely to affect the process of behavioural recovery.

Animals↗

Vestibular influences on CA1 neurons in the rat hippocampus: an electrophysiological study in vivo.

Vestibular information is known to be important for accurate spatial orientation and navigation. Hippocampal place cells, which appear to encode an animal's location within the environment, are also thought to play an essential role in spatial orientation. Therefore, it can be hypothesized that vestibular information may influence cornu ammonis region 1 (CA1) hippocampal neuronal activity. To explore this possibility, the effects of electrical stimulation of the medial vestibular nucleus (MVN) on the firing rates of hippocampal CA1 neurons in the urethane-anesthetized rat were investigated using extracellular single unit recordings. The firing rates of CA1 complex spike cells (n=29), which most likely correspond to place cells, consistently increased during electrical stimulation of the MVN in a current intensity dependent manner. Stimulation applied adjacent to the MVN failed to elicit a response. Overall, the firing rates of non-complex spike cells (n=22) did not show a consistent response to vestibular stimulation, although in some cells clear responses to the stimulation were observed. These findings suggest that vestibular inputs may contribute to spatial information processing in the hippocampus.

Animals↗