Bilateral Common Carotid Ligation Research Articles

Bone-marrow cell therapy induces differentiation of radial glia-like cells and rescues the number of oligodendrocyte progenitors in the subventricular zone after global cerebral ischemia

The subventricular zone (SVZ) is recognized as one of the neurogenic regions in the adult mammalian central nervous system and the presence of cells that share similar characteristics with developmental radial glia, the radial glia-like cells (RGLCs) has been demonstrated in this region. In this study, we investigated whether and how SVZ cells respond to global ischemia and/or to the intravenous transplant of bone-marrow mononuclear cells (BMMCs). Adult rats were subjected to bilateral common carotid ligation (BCCL) and after 1day 2×107 BMMCs or saline injection. The BMMC transplant stimulated a transitory increase in the proliferation of SVZ cells in the BCCL group. We observed a significant increase in the number of RGLCs 3days after ischemia, in both BCCL and BCCL+BMMC groups. However, this increase persisted in the subsequent days only in BCCL animals that received the transplant. BMMC transplantation also inhibits the reduction of NG2-positive oligodendrocyte progenitors in the SVZ observed in the BCCL group. Interestingly, brain-derived neurotrophic factor (BDNF) expression was up-regulated in the SVZ in the treated animals, but not in the other groups. These data thus suggest that BMMC transplantation modulates the phenotype of RGLCs/progenitors in the SVZ and could have a protective role after ischemia.

Inhibitory effect of vasopressin receptor antagonist OPC-31260 on experimental brain oedema induced by global cerebral ischaemia

The effects of the non-peptide vasopressin V(2) receptor antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6 h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma vasopressin level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma vasopressin level was further enhanced by OPC-31260. These results demonstrate the important role of vasopressin in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal vasopressin V(2) receptors. These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

In Vivo Gene Transfer to Cerebral White Matter Lesions with a Recombinant Adenovirus Vector

Ischemic white matter lesions have been reported in rats after bilateral common carotid ligation (BCAL). Previously, comparing normotensive rats (WKY) with spontaneously hypertensive rats (SHR), we too found that sustained moderate ischemia with spontaneous hypertension accelerated the formation of ischemic white matter lesions. In this study, we explored the feasibility of gene therapy for lesioned white matter by means of an adenovirus vector expressing a reporter gene, LacZ. Using sham-operated and hypoperfused SHR as well as sham-operated and hypoperfused WKY, we demonstrated that (i) adenovirus vectors could deliver a foreign gene into oligodendrocytes and astrocytes in the cerebral white matter; (ii) the transduction efficiency was most effective in SHR after BCAL; and (iii) the level of αV-integrin was significantly correlated with adenoviral transduction efficiency.

Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats

To investigate the influence of cerebral hypoperfusion on learning behaviours, we developed a novel rat cerebral hypoperfusion model, in which the bilateral internal carotid arteries were permanently ligated to reduce the cerebral blood flow, and examined its behavioural and histopathological consequences in comparison to those occurring after bilateral common carotid ligation. In the Morris water maze task, rats with common carotid ligation exhibited a learning deficit, whereas rats with internal carotid ligation exhibited normal learning. Both models exhibited significant learning impairments in the eight-arm radial maze task, although the impairment was less severe in internal carotid-ligated rats than in common carotid-ligated rats. The cerebral blood flow of rats with common carotid ligation was reduced significantly both two and 10 days after ligation, and was still below normal three months after ligation. A milder, but significant reduction in the cerebral blood flow was observed in internal carotid-ligated rats. Shrinkage of the optic nerves and a circadian activity rhythm desynchronized to the light/dark cycle were exhibited by the rats with common carotid ligation, whereas these parameters remained unaffected in the rats with internal carotid ligation, suggesting that permanent ligation of common carotid arteries but not internal carotid arteries impairs visual functions. The main pathological changes observed in the brain following common carotid ligation were rarefaction and gliosis of the white matter and neuronal loss in the hippocampal CA1 region. On the other hand, the rats with internal carotid ligation had no significant brain damage. Chronic treatment with idebenone (1.5 and 15 mg/kg/day), a cerebral energy metabolism enhancer, over a three-month period, commencing five days after ligation, ameliorated the impairment of water maze learning in rats with common carotid ligation. The treatment also significantly improved the learning impairment in the radial maze task of internal carotid-ligated rats. Idebenone had no effect on the histopathological changes that followed cerebral hypoperfusion. It is concluded that cerebral hypoperfusion induced by permanent internal carotid ligation impairs the working memory without causing pathological damage to the brain tissues and the visual system, and the learning impairment can be ameliorated by a cerebral energy metabolism enhancer. These findings have the clinical implication that a reduction in blood flow may be an important factor that causes or exacerbates cognitive decline in dementias.

The role of histamine in brain oedema formation.

The effects of histamine on the cerebral endothelial cells were studied. To determine if the extent of brain oedema formation could be reduced with histamine receptor antagonists, mepyramine (H1-receptor blocker), metiamide, cimetidine and ranitidine (H2-receptor antagonists) were administered at a dose of 5 mg/kg body weight 4, 2 and 0 h before the onset of experimental pneumothorax induced in newborn piglets. Mepyramine and ranitidine given 2 h before the induction of EBP prevented the accumulation of water, sodium and albumin in samples taken from the parietal cortex. In other experiments, carried out on Sprague-Dawley rats of CFY strain after permanent bilateral common carotid ligation (BCCL), the accumulation of water and sodium in the ischemic brain tissue could also be prevented in a dose dependent manner by intraperitoneal injections of ranitidine given 30 min before the surgery. Taken together, these results provide pharmacological evidence for the involvement of histamine receptors in the pathogenesis of brain oedema. Consequently, the use of histamine receptor blockers both in the prevention and in the treatment of brain oedema can be recommended.

Trophic changes in the arteries at the base of the rat brain in response to bilateral common carotid ligation.

A rat model was developed to examine changes in the posterior circle of Willis and the basilar and intracranial vertebral arteries after bilateral common carotid ligation. This procedure produced a major redistribution of blood to the head, with increased flow through the vertebral and basilar arteries. Changes in the vertebral, basilar, posterior communicating and proximal segments of the posterior cerebral arteries and neck vessels were assessed by postmortem barium sulfate arteriography and by histology of the middle portion of the basilar arteries serially at four days, and one, two, four and 15 weeks post-ligation. The changes noted were basilar and vertebral artery tortuosity, enlargement, and duplication of the vertebro-basilar junction. By 15 weeks, these intracranial vascular changes had largely regressed toward normal, commensurate with the appearance of multiple collateral vessels which were scattered throughout the soft tissues of the neck and shunted the original ligation sites. A mechanism that could explain these trophic vessel changes in response to increased blood flow is discussed. Some possible correlates of these findings with several brain vascular diseases are presented.

Effect of indapamide on an experimental model of cerebral ischemia in hypertensive rats

This study quantified the immediate general hemodynamic events following the bilateral carotid ligation-induced cerebral ischemia in normotensive and spontaneously hypertensive rats. The influence of treatment with indapamide was evaluated. In normotensive rats, hemodynamic values remained unchanged during the 10 minutes following the carotid ligation. In spontaneously hypertensive rats, arterial pressure values immediately and significantly (p <0.01) increased, up to 50 percent during the 10 minutes following the carotid ligation. Heart rate was unchanged. Indapamide at a short-term 3 mg/kg intraperitoneally, chosen in order to give a minimal (non-significant) antihypertensive effect in spontaneously hypertensive rats, significantly (p <0.01) reduced the bilateral carotid ligation-induced vasopressor response, whereas heart rate remained unchanged. The results presented here show that in spontaneously hypertensive rats, but not in normotensive rats, bilateral common carotid ligation induces an immediate and strong increase in arterial pressure values. These results compare with the previously described differences in cerebral ischemia-induced disorders in normotensive and hypertensive rats. Finally, indapamide, an antihypertensive agent that decreases vascular reactivity, significantly inhibits the carotid ligation-induced vasopressive response in hypertensive rats.

Effect of indapamide on an experimental model of cerebral ischemia in hypertensive rats

This study quantified the immediate general hemodynamic events following the bilateral carotid ligation-induced cerebral ischemia in normotensive and spontaneously hypertensive rats. The influence of treatment with indapamide was evaluated. In normotensive rats, hemodynamic values remained unchanged during the 10 minutes following the carotid ligation. In spontaneously hypertensive rats, arterial pressure values immediately and significantly (p less than 0.01) increased, up to 50 percent during the 10 minutes following the carotid ligation. Heart rate was unchanged. Indapamide at a short-term 3 mg/kg intraperitoneally, chosen in order to give a minimal (nonsignificant) antihypertensive effect in spontaneously hypertensive rats, significantly (p less than 0.01) reduced the bilateral carotid ligation-induced vasopressor response, whereas heart rate remained unchanged. The results presented here show that in spontaneously hypertensive rats, but not in normotensive rats, bilateral common carotid ligation induces an immediate and strong increase in arterial pressure values. These results compare with the previously described differences in cerebral ischemia-induced disorders in normotensive and hypertensive rats. Finally, indapamide, an antihypertensive agent that decreases vascular reactivity, significantly inhibits the carotid ligation-induced vasopressive response in hypertensive rats.

Vascular permeability and the optic disc. Changes after bilateral common carotid ligation in the rat.

The permeability of retinal blood vessels to intravenously injected horseradish peroxidase was examined two to seven days after bilateral common carotid ligation in rats. Light and electron microscopy revealed leakage from the blood vessels of the optic disc. This leakage appeared to result from vesicular transport across the endothelium; the interendothelial tight junctions we examined remained intact and there was no evidence of endothelial cell death. The intraretinal blood vessels and the retinal pigment epithelium retained their normal impermeability to horseradish peroxidase. Cellular edema was present at the optic disc, manifested as swollen axons. Glial cells remained normal in appearance and the extracellular space was not enlarged. These observations clarify those previously derived from funduscopy and fluorescein angiography, which revealed disc edema and hyperfluorescence.

Metabolic disturbances of synaptosomes isolated from ischemic gerbil brain.

The effects of cerebral ischemia, induced for 10 min by bilateral common carotid ligation in the Mongolian gerbil, on the brain and synaptosomal content of phospholipids and free fatty acids were measured. Moreover, the incorporation of arachidonic acid and oleoyl-CoA into phospholipids, as well as the respiration and the accumulation of 45Ca, norepinephrine, dopamine, choline, glutamate, and gamma-aminobutyrate in the ischemic brain synaptosomal fraction were studied. Analyses of lipids showed a drop in phospholipids content with concomitant increase of lysocompounds and free fatty acids in ischemic cerebral cortex. Disturbances in lipid metabolism including rapid phospholipids hydrolysis and changes in the incorporation of arachidonic acid into inositol and choline phosphoglycerides were also shown in the synaptosomal fraction of ischemic brain. The uptake of neurotransmitter substances, expressed as a percent of control value, was reduced 21% for norepinephrine, 40% for dopamine, 20% for choline, 24% for glutamate and 13% for gamma-aminobutyrate in ischemic synaptosomes. There was no significant effect of ischemia on synaptosomal respiration and 45Ca uptake in both control and high potassium media. The inhibition of neurotransmitter uptake in ischemic brain synaptosomes may be caused by the disturbance of fatty acid metabolism.

Changes of Brain Catecholamines in SHR following Bilateral Common Carotid Ligation

It was demonstrated that the levels of brain CA were higher in SHR than NTR and that CA levels and turnover rates in SHR were changed during brain ischemia following BCL. Because of increase of DA in contrast to NA, brain ischemia in SHR may cause lowering activity of dopamine-β-hydroxylase rather than that of tyrosine hydroxylase. Futhermore, the fact that characteristic behaviors related to decreases of CA during ischemia, for example rolling, circling and jumping, occured after 3h of BCL and later in spite of increases of DA may probably reflect changes of DA receptors in SHR.Those results may he summarized that there are some abnormalities of brain CA system, including receptors, in SHR.