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K Horsburgh

Publications and source records attributed to K Horsburgh.

26 records · Page 2Linked to original sources
PubMed1993

Focal increases in [3H]forskolin and [3H]phorbol 12,13-dibutyrate binding in the rat brain following lesions of the medial septum.

Quantitative autoradiography of [3H]forskolin binding to GS-adenylate cyclase and [3H]phorbol 12,13-dibutyrate (PDBu) binding to protein kinase C (PKC) was examined 21 days following ibotenate lesion of the rat medial septum. A significant reduction (-19%) in [3H]forskolin binding was observed at the lesion site in the medial septum compared to the sham-treated group. A significant increase in [3H]forskolin binding was demonstrated in the polymorph layer of the detante gyrus (19%) in animals with medial septal lesions whilst in all other brain regions, [3H]forskolin binding remained unaltered post-lesion. [3H]PDBu binding was significantly increased in the superficial layers (I-III) of entorhinal cortex (27%) following lesion of the medial septum, and remained unaltered in all other brain regions post-lesion. The nature and location of the alterations (namely elevations) in ligand binding sites remote from the lesioned area are supportive of plastic modifications of second messenger systems following denervation.

Adenylyl Cyclases↗
PubMed1991

Differential alterations of second messenger systems and cerebral glucose use following excitotoxic lesion of rat cerebral cortex.

Quantitative autoradiography of [3H]forskolin and [3H]phorbol 12,13 dibutyrate (PDBu) binding was examined 21 days after unilateral lesioning of the rat visual cortex using ibotenic acid. In the same animals, the functional deficit was assessed using quantitative [14C]-2-deoxyglucose autoradiography. [3H]Forskolin binding was significantly reduced in each layer of the lesioned visual cortex by at least 40% compared to the contralateral hemisphere. Significant reductions in [3H]forskolin binding were observed in the superior colliculus (-15%) and dorsal lateral geniculate body (-12%) ipsilateral to the lesioned cortex. [3H]PDBu binding was significantly reduced in the lesioned visual cortex (layers V-VI) by 34%, compared with the control hemisphere. There were no significant alterations in [3H]DPBu binding in any other brain regions. Following ibotenate-induced lesioning of the visual cortex, glucose use was significantly reduced throughout the lesioned cortex by at least 25% with minor alterations in glucose use in the ipsilateral dorsal lateral geniculate body and superior colliculus. The present study highlights the relative robustness of [3H]PDBu binding compared to [3H]forskolin binding after excitotoxic damage to the cerebral cortex and suggests that [3H]forskolin binding sites are present on cortical efferent fibres.

Animals↗
PubMed1991

Alterations of functional glucose use and ligand binding to second messenger systems following unilateral orbital enucleation.

Quantitative autoradiography was used to examine the effect of lesioning a well-defined glutamatergic system (retinofugal fibres) on [3H]forskolin binding to Gs-adenylate cyclase and [3H]PDBu (phorbol-12,13-dibutyrate) binding to protein kinase C (PKC) in the rat visual system at 1, 5, 10 and 20 days after unilateral orbital enucleation. Local cerebral glucose utilisation was determined in the same animals using quantitative [14C]2-deoxyglucose autoradiography. At 5 days post-lesion, [3H]forskolin binding sites were significantly reduced in the visually-deprived superior colliculus (-14 +/- 1%) and dorsal lateral geniculate body (-8 +/- 2%), and these reductions persisted until 20 days post-lesion. There were no significant alterations in the amount of [3H]PDBu binding in any region in the visually-deprived hemisphere following enucleation. Function-related glucose use was significantly reduced throughout the visual pathway after enucleation. In this study, there was no conclusive evidence of plastic modifications of second messenger systems in the rat visual system despite a general depression of visual function following lesion of retinofugal fibres.

Adenylyl Cyclases↗
PubMed1991

Autoradiographic imaging of [3H]phorbol 12,13-dibutyrate binding to protein kinase C in Alzheimer's disease.

Quantitative autoradiography was used to examine the distribution of [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding to protein kinase C in the middle frontal and temporal cortices and the hippocampal region of nine control and nine elderly subjects with Alzheimer's disease (AD). AD patients had a clinical diagnosis of the disease that was confirmed neuropathologically by the presence of numerous plaques in the hippocampus and cerebral cortex. Choline acetyltransferase (ChAT) activity was significantly reduced in the middle frontal and temporal cortex and in the hippocampus of AD subjects, with the deficit being greater than 60% of control values. Quantitative autoradiographic analysis of [3H]PDBu binding to protein kinase C revealed a heterogeneous pattern in control brain, being particularly high in superficial layers of the cortex and CA1 of the hippocampus. There were no significant differences between control and AD sections in all areas examined within the middle frontal cortex; e.g., layers I-II control, 491 +/- 46 versus AD, 537 +/- 39 pmol/g of tissue; middle temporal cortex, e.g., layers I-II control, 565 +/- 68 versus AD, 465 +/- 72 pmol/g of tissue; and hippocampal formation, e.g., CA1 control, 511 +/- 28 versus AD, 498 +/- 25 pmol/g of tissue. In a parallel study, [3H]PDBu binding to homogenate preparations of control and AD brain confirmed that there was no significant difference in [3H]PDBu binding in either the particulate or the cytosolic fraction. We have demonstrated in a well-defined population of AD patients that [3H]PDBu binding to protein kinase C remains preserved in brain regions that are severely affected by the neuropathological and neurochemical correlates of AD.

Alzheimer Disease↗
PubMed1990

Second messenger systems: functional role in cerebrovascular smooth muscle regulation.

The role of two second messenger systems in alterations of cerebrovascular smooth muscle tone was examined in feline cerebral arteries using an in vitro preparation of vessel segments and cortical pial vessels in situ. Forskolin, which is known to activate adenylate cyclase, elicited a concentration-dependent relaxation of arteries preconstricted with prostaglandin F2 alpha (PGF2 alpha) (EC50 was approximately 300 nM). Microapplication of forskolin around individual cortical arteries and arterioles in situ elicited a dose-dependent dilatation. The maximum increase in arteriolar calibre was 54 +/- 4% from pre-injection calibre and EC50 was approximately 100 nM. Phorbol 12,13 dibutyrate (PDBu), which activates protein kinase C, elicited strong contractions of cerebral vessels. In vitro, PDBu contracted vessel segments in a concentration-dependent manner (EC50 was approximately 100 nM). Similarly, PDBu elicited potent dose-dependent constriction of pial arterioles in situ. The maximum response to PDBu was a 37 +/- 5% reduction in arteriolar calibre and the concentration eliciting EC50 was approximately 100 nM. These data provide an assessment to capacity of feline cerebral arteries to dilate and contract in response to adenylate cyclase and protein kinase C activation respectively.

Animals↗
PubMed1990

Selective alterations of high affinity [3H]forskolin binding sites in Alzheimer's disease: a quantitative autoradiographic study.

Quantitative autoradiographic analysis of high affinity [3H]forskolin binding sites was carried out in postmortem brains from normal controls and patients dying with Alzheimer's disease. Choline acetyltransferase (ChAT) activity and senile plaque formation were also quantified. [3H]Forskolin binding was markedly reduced in all layers of middle frontal gyrus in the Alzheimer brains and the deficit correlated with the deficit in ChAT activity in this area. In the hippocampal region [3H]forskolin binding was no different in the Alzheimer brains compared to controls, although ChAT activity was significantly reduced. There was an inconsistent reduction in [3H]forskolin binding in all layers of middle temporal gyrus which did not correlate with the cholinergic deficit. Significant senile plaque formation was observed in all 3 brain regions examined and [3H]forskolin binding did not correlate with plaque formation in any brain region. Thus, while all 3 brain regions were affected by the pathological correlates of Alzheimer's disease, [3H]forskolin binding was consistently reduced only in frontal cortex.

Adenylyl Cyclases↗
PubMedDate not supplied

The role of apolipoprotein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models.

The epsilon 4 allele of apolipoprotein E (APOE denotes gene; apoE denotes protein) is a major risk factor for Alzheimer's disease (AD). More recent evidence indicates an association with a poor outcome after acute brain injury including that due to head trauma and intracerebral hemorrhage. APOE gene polymorphism also influences the risk of hemorrhage in cerebral amyloid angiopathy. These diverse brain disorders seem to have some mechanisms in common. The multiplicity of the roles of apoE within the central nervous system is currently being unraveled. For example, apoE can interact with amyloid beta-protein and tau, proteins central to the pathogenesis of AD. In addition to these effects, it is proposed that one of the major functions of apoE is to mediate neuronal protection, repair and remodeling. In all of the different roles proposed, there are marked apoE-isoform specific differences. Although it remains to be clarified which is the most important mechanism(s) in each disorder in which apoE is involved, these isoform specific differences seem to underly a genetically determined susceptibility to outcome from acute brain injury and to AD with APOE epsilon 4 conferring relative vulnerability. This review focuses on apoE research, from clinical studies to animal models, in AD, acute brain injury and cerebrovascular disease and explores the common mechanisms that may explain some of the complex underlying neurobiology.

Alzheimer Disease↗