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G Arbuthnott

Publications and source records attributed to G Arbuthnott.

14 recordsLinked to original sources
PubMed1999

Acute in vivo neurotoxicity of peptides from Maedi Visna virus transactivating protein Tat.

Lentiviruses such as Maedi Visna virus (MVV) in sheep, and human immunodeficiency virus (HIV) in man often cause a variety of neurological syndromes in later stages of infection. Neuropathological investigations reveal damage to myelin and astrocytosis in both white and grey matter. MVV infection induces axonal damage with some areas of necrosis while neuronal loss, and synaptic damage have been reported in HIV-1 infection. It is not clear, at present, how this neurodegeneration is mediated but, as these viruses do not directly infect neurons, an indirect neurotoxic action of the viruses is indicated. Previous experiments have shown that the intra-striatal injection in rats of a synthetic peptide derived from the basic region of the MVV transactivating protein Tat causes considerable neurotoxicity 1 week post-operatively. By in vivo stereotaxic injections of the same synthetic peptide, and subsequent immunocytochemical detection of neurons, astrocytes and microglia, we show that this neurotoxicity displays a distinctive and unusual lesion profile and is evident as rapidly as 0.5 h post-operatively. Furthermore, neuroprotection studies suggest that the early effects of the MVV tat peptide may involve glutamate neurotoxicity via the N-methyl-D-aspartate (NMDA) receptors since the application of dizolcipine (MK801) reduces the volume of the lesion seen at 1 h after the injection of neurotoxic peptide, while L-NAME is ineffective. The mechanism of this early neurotoxicity is thus different from the longer term actions already described.

Amino Acid Sequence↗
PubMed1995

Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus.

Infection by lentiviruses such as human immunodeficiency virus (HIV) and Maedi-Visna virus (MVV) is associated with neurodegenerative disorders. We have investigated the neurotoxic mechanisms of a synthetic peptide of transactivating protein tat of MVV in striatal neuronal cultures. Tat peptide (but not control peptide) caused neuronal death, without affecting glial viability, in a time- and dose-dependent manner. Significant neuronal death was not observed until 6-8 h after tat peptide application (2.35-2350 nM), whereas half maximal and maximal cell death was observed after 12 and 24 h respectively. Tat peptide neurotoxicity could be partially inhibited by blockade of either N-methyl-D-aspartate (NMDA)- or non-NMDA receptors, suggesting that excessive neuroexcitation by glutamate or its analogues may contribute to tat-neurotoxicity. Furthermore, when both these glutamate receptor subtypes were blocked simultaneously, an increased degree of neuroprotection was observed. Finally, tat peptide toxicity was also reduced by blockade of L-type calcium channels. Calcium imaging revealed that intracellular calcium increases slowly upon tat application, predominantly due to entry of extracellular calcium. These results indicate that cellular calcium entry through voltage-gated calcium channels following activation of both NMDA and non-NMDA receptors, and subsequent accumulation of intracellular calcium may contribute to the neuronal death induced by tat protein.

Animals↗
PubMed1994

The basic domain of the lentiviral Tat protein is responsible for damages in mouse brain: involvement of cytokines.

The HIV and visna lentiviruses induce an inflammatory reaction in the central nervous system (CNS) of the infected hosts leading to dysmyelination, demyelination, and neuronal loss. The basic domain of the transactivating Tat protein has been involved in CNS damage. Infusion of basic containing domain Tat peptides in the lateral ventricle (systemic injection) or in the grey matter, i.e., hippocampus and thalamus (local injection), induced an inflammatory process characterized by the formation of an edema and invasion of macrophage accompanied by reactive astrogliosis. Control peptides originating from either lentiviral proteins or irrelevant protein as ovalbumin did not lead to any inflammatory reaction or cell death. The inflammation led to the loss of ependymal cells in the lateral ventricles and neurons in the grey matter. RNA extracted from the Tat-injected hemisphere reacted with TNF-alpha, IL-1 alpha and beta, and IL-6 probes. The macrophage/microglia inducible nitric oxyde synthase was also expressed. Blockade of TNF-alpha by a pentoxifylline treatment led to the decrease of IL-1 and iNOS expression accompanied by a reduction of the volume of the lesions indicating that the Tat-induced lesions might be mediated by TNF production.

Amino Acid Oxidoreductases↗
PubMed1993

Neurotoxicity of peptide analogues of the transactivating protein tat from Maedi-Visna virus and human immunodeficiency virus.

Infection by lentiviruses such as human immunodeficiency virus, Maedi-Visna virus and Caprine Arthritis Encephalitis Virus, is associated with a variety of neurological syndromes, but the mechanism by which the damage occurs to the nervous system is not known. The viruses do not infect neurons and so the neurotoxic actions must be mediated indirectly. Here we applied synthetic peptide analogues derived from basic regions of Maedi-Visna virus and human immunodeficiency virus transactivating protein, tat, to rat brain in vivo and found them to be potent neurotoxins. The toxicity of the Maedi-Visna virus peptide was demonstrated to be reduced by blockade of nitric oxide synthase and of N-methyl-D-aspartate channel opening. These experiments suggest that peptides derived from lentiviral tat may share a common neurotoxic action.

Amino Acid Oxidoreductases↗
PubMed1993

Distribution of thyrotrophin-releasing hormone receptor messenger RNA in rat pituitary and brain.

The distribution sites of messenger RNA encoding for the thyrotrophin-releasing hormone receptor have been studied in rat pituitary and brain. A specific 35S-labelled riboprobe generated from a rat thyrotrophin-releasing hormone receptor complementary DNA clone was used to perform in situ hybridization experiments on brain and pituitary sections. A positive hybridization signal was found in the anterior lobe of the pituitary gland, the intermediate and posterior lobes were negative. Hybridization was also detected in different areas of the brain. These areas include distinct regions in the olfactory system, septal area, amygdaloid complex, cerebral cortex, hypothalamus, hippocampus, basal ganglia and the motor nuclei of cranial nerves in brainstem. This study has shown for the first time the exact site of thyrotrophin-releasing hormone receptor expression in the central nervous system. These results correlate well with regions thought to possess thyrotrophin-releasing hormone recognition sites.

Animals↗
PubMed1989

The influence of the estrous cycle on the activity of striatal neurons recorded from freely moving rats.

Recordings from striatal neurons in conscious rats at various stages of the estrous cycle revealed differences in the activity of the neurons. Average firing rate was higher in diestrus than in animals in estrus or proestrus. The increase did not seem to depend on the motor activity of the animals nor was it present in ovariectomized rats. Since application of estrogen to ovariectomized rats did not change the firing rate of the neurons, we conclude that differences during the cycle in conscious rats are not mediated by an action of estrogen unlike those seen in anesthetized rats. Differing electrode sampling bias in the two situations, or an action of anesthetic in revealing the estrogen effect may explain the differences.

Action Potentials↗
PubMed1988

Graft-derived recovery from 6-OHDA lesions: specificity of ventral mesencephalic graft tissues.

A series of experiments have been conducted to assess the specificity of recovery from motor asymmetries that is provided by dopamine-rich grafts in the neostriatum of rats with unilateral dopamine-depleting lesions produced by injection of 6-hydroxydopamine into the ascending nigrostriatal pathway. Grafts of embryonic tissue taken from the substantia nigra (rich in dopamine neurons could provide a complete recovery of methamphetamine-induced rotation and a partial recovery of apomorphine-induced rotation, whereas no recovery was seen in rats with grafts of tissue rich in another monoamine (serotonin, dissected from the mesencephalic raphe) or of tissue appropriate to the target (dissected from the striatal eminence). 6-Hydroxydopamine lesions of dopamine cells in the grafts of recovered animals reinstated the initial lesion-induced asymmetry. Dopamine-rich grafts implanted into the intact neostriatum did not induce any "supernormal" asymmetry in the rats, but did provide a "prophylactic" protection against subsequent lesions of the intrinsic ipsilateral dopamine nigrostriatal system. Post-mortem biochemical assays indicated that the extent of dopamine depletion in the neostriatum of lesioned rats correlated highly with both methamphetamine and apomorphine turning rates. Similarly, both drug rotation tests correlated significantly with the extent of dopamine restoration in the dorsal striatum of rats with dopamine-rich grafts, the correlation being significantly higher for the methamphetamine than for the apomorphine test.

Acetylcholinesterase↗
PubMed1985

Electrophysiological properties of single units in dopamine-rich mesencephalic transplants in rat brain.

Electrophysiological recordings were made from grafts of embryonic ventral mesencephalon transplanted into the neocortex, overlying the host neostriatum of rats in which the intrinsic striatal dopamine (DA) innervation had been removed by a unilateral 6-hydroxydopamine (6-OHDA) lesion. Whereas all rats had surviving grafts, half of the rats showed recovery from amphetamine-induced rotational asymmetry induced by the 6-OHDA lesions ('compensation'), indicating a functional dopaminergic reinnervation of the host striatum by the graft. The electrophysiological recordings revealed: neurons within all grafts which could be antidromically activated from host striatum, and which had faster conduction velocities and narrower action potentials than is characteristic of DA neurons in the intact substantia nigra, neurons only within the grafts of compensated rats which had properties characteristic of normal nigral DA neurons, and neurons within the grafts which responded to stimulation of the frontal cortex and lower brainstem of the host. The data support the view that the grafts can establish physiologically functional afferent and efferent connections with the host brain.

Animals↗
PubMed1979

Characterization of immunofluorescent cyclic GMP-positive fibres in the central nervous system.

The cyclic GMP immunofluorescent fibres in the rat central nervous system have been characterized as processes of fibrous astrocytes, on the basis of distribution and similarity to the localization of glial fibrillary acidic protein. The neuroglial localization of the nucleotide is discussed together with the surprising observation that these cyclic GMP positive fibres are absent from the central nervous system of the adult mouse.

Animals↗
PubMedDate not supplied

Some non-fluorescent connections of the nigro-neostriatal dopamine neurones.

This study of the relationships between cells identified by their catecholamine fluorescence and their less fortunate neighbours became possible with the advent of autoradiographic tracing methods. A major output from the neostriatum returns to the substantia nigra where it fills the pars reticulata. Outputs from this area of substantia nigra are present on both sides of the brain in the thalamus, in parts of parafascicular, intralaminar, and mediodorsal nuclei, and the superior colliculi in the deeper layers. Mainly unilateral pathways reach the ventromedial nucleus of thalamus and also pass under the lateral part of the colliculus to reach the region of the nucleus pendunculo-pontinus among the fibres of the brachium conjunctivum. The roles of those areas in the transmission of the output of the basal ganglia to the motor system of the animal, however, remain obscure.

Animals↗