Current Neurovascular Research - Volume 5, Issue 1, 2008

Chronic stress and increased sympathetic nerve activity have been associated with cardiovascular disorders such as hypertension, myocardial infarction and stroke. The aim of this study was to investigate the role of nerve growth factor (NGF) on the expression of tyrosine hydroxylase (TH), vascular-endothelial growth factor (VEGF) and leptin receptor (OB-R) in brain, adrenal and cardiovascular tissues of adult male and female mice following a chronic stress procedure. It was found that daily restraint for 10 consecutive days alters TH levels in hypothalamic and brainstem areas related to sympathetic activation, in both male and female mice. Chronic stress procedure also modifies heart and aorta VEGF levels in male mice, and adrenal glands TH in female mice. The NGF administration in stressed mice reverted the stress-induced up-regulation of TH levels in male and female mice hypothalamic nuclei and in male locus coeruleus. Administration of NGF in stressed animals also down-regulated OB-R levels in the hypothalamus of both male and female mice and in the female aorta. Our findings indicate that repeated restraint in mice has an effect on TH and VEGF protein content at different brain and peripheral sites involved in the sympathetic and cardio-vascular response to stressful stimuli. NGF administration is able to counteract some of these stress-induced changes. Since NGF is known to be up-regulated during stress, a possible functional significance of our observations is that the circulating NGF released during and following stress may serve to prevent possible deficits and/or damage linked to stress-induced sympathetic and cardiovascular activation.

The current study investigated whether chronic cerebral hypoperfusion produced by permanent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) induced cognitive impairment and whether angelica injections alleviated the impairment. Furthermore, the study examined whether 2-VO altered the expression patterns of brainderived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of rats and whether angelica injections attenuated the alteration. Rats were divided into four groups to receive either 2-VO surgery or sham surgery followed by either angelica injections or saline injections for eight weeks. Spatial learning in Morris water maze and the expression patterns of BDNF and NGF in the hippocampus of all rats were examined. The results showed that 2-VO significantly impaired spatial learning and memory, and angelica injections significantly reversed the learning and memory impairment. Furthermore, 2-VO resulted in significantly decreased BDNF protein, NGF protein, and NGF mRNA expression in the hippocampus. Angelica injections significantly attenuated the decreased expression. Moreover, spatial learning in Morris water maze was positively correlated to the expression of BDNF and NGF in the hippocampus. Thus, angelica injections might alleviate cognitive impairment during chronic cerebral hypoperfusion through BDNF and NGF.

Molecular accounts of memory consolidation suggest that new learning generates persistent synaptic modifications through activation of an extensive set of neuronal receptors and intracellular signal transduction pathways, accompanied by RNA and protein synthesis. This traditional cellular consolidation theory has been challenged by evidence that reactivation of a previously consolidated memory might render this memory again susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation. Current evidence indicates that reconsolidation can be disrupted by administration of a variety of pharmacological agents after memory reactivation. Previous studies have indicated that the gastrin-releasing preferring type of bombesin receptor (GRPR) and the N-methyl-D-aspartate glutamate receptor (NMDAR) in the rat hippocampus are involved in consolidation of inhibitory avoidance (IA), a fear-related memory task. We show here that blockade of hippocampal GRPRs or NMDARs after memory reactivation temporarily disrupts memory retention. Post-retrieval intra-hippocampal infusion of the GRPR antagonist RC-3095 or the NMDAR antagonist aminophosphonopentanoic acid (AP5) produced an impairment of IA performance tested 2 days after training in rats. However, this impairment was transient and recovered to levels of control rats in a subsequent test 3 days after training. The drug effects were only present after memory reactivation and not in its absence. These findings provide evidence that GRPR or NMDAR inactivation after retrieval can impair fear memory.

Atherosclerosis may cause severe stenosis of the arteries supplying the brain, which induces chronic cerebral hypoperfusion. Although an infarction often occurs in this area, it is uncertain how brain vessels respond to the chronic hypoperfusion or how the vascular responses are related to stroke severity when the area has been subjected to severe ischemia. To address these uncertainties, we induced chronic cerebral hypoperfusion in Sprague-Dawley rats with a bilateral common carotid artery ligation (BCAL). A middle cerebral artery occlusion/reperfusion (MCAO/R) was introduced with a nylon suture four weeks after either BCAL (BCAL-MCAO) or a sham operation (Sham-MCAO). Motor disability scores and infarct sizes, based on 2,3,5-triphenyltetrazolium chloride staining, were significantly reduced with BCALMCAO treatment compared with sham-MCAO treatment (P<0.01). The diameters of the posterior cerebral, posterior communicating, and basilar arteries on the brain surface were larger and more tortuous in BCAL-treated rats (P<0.01). The density of large capillary- and arteriole-sized vessels in the brain parenchyma also increased in BCAL-treated rats (P<0.05). Strokes were less severe when the vicinity subjected to infarction was preconditioned with chronic cerebral hypoperfusion. Increasing the vascular reserve with adaptive vascular remodeling may have contributed to this response.

Cerebral aneurysm (CA) causes a life-threatening subarachnoid hemorrhage. However, no effective medical treatment to prevent the growth of CA is available. Nifedipine, a widely used calcium antagonist, was shown to improve endothelial function in various cardiovascular diseases. We examined whether nifedipine has a protective effect on CA progression. CAs were experimentally induced in Sprague-Dawley rats followed by intraperitoneal injection of either 10mg/kg of nifedipine per day or vehicle. The size and media thickness of CAs were measured one month after aneurysm induction. NF-kappa B (NF-κB) activity in aneurysmal walls was assessed by immunohistochemistry for activated NF-κB p65 subunit and electrophoretic mobility shift assay (EMSA). Expression of monocyte chomoattractant protein-1 (MCP- 1) and matrix metalloproteinase (MMP) -2 in aneurysmal walls was examined by RT-PCR and immunohistochemistry. To examine whether nifedipine has a suppressive effect on preexisting CAs, nifedipine administration started at one month after aneurysm induction and pathological changes were assessed at two months after aneurysm induction. Aneurysm size was smaller and the media was thicker in the nifedipine-treated group even though blood pressure was not different between groups. Nifedipine inhibited DNA binding of NF-κB in aneurysmal walls. As regards MCP-1 expression and macrophage, which is the main inflammatory cell in the aneurysmal walls, infiltration into aneurysmal walls was decreased by nifedipine. Immunohistochemistry and gelatin zymography showed that the expression and activity of MMP-2 was also reduced by nifedipine. Furthermore, nifedipine significantly prevented the enlargement and degeneration of aneurysmal walls of preexisting CAs. Nifedipine may be useful as a medical drug for patients with CAs.

Spinal cord injury remains a devastating complication of thoracic and thoracoabdominal aortic operations. We aimed to investigate neuro-protective role of melatonin administered to rabbits before ischemia against ischemiareperfusion (IR) injury. Occlusion of the abdominal aorta was applied to adult rabbits, followed by removal of aortic clamp and reperfusion. The abdominal aortas of New Zealand White albino rabbits (n = 18) were occluded for 30 minutes. Experimental groups were as follows: control group (sham operation group, n =10), Ischemia/reperfusion group (I/R) (n = 10) undergoing occlusion but receiving no pharmacologic intervention, Melatonin-treated group (n = 8) receiving 10mg/kg melatonin intravenously 10 minutes before ischemia. Neurologic status was assessed at 6, 24, and 48 hours after the operation. Spinal cords were harvested for histopathologic and biochemical analyses. Melatonin-treated animals had better neurologic function than those of the I/R group. Decreased tissue and serum malondialdehyde (MDA) levels and increased tissue and serum glutathione (GSH) levels were observed in melatonin-treated group (p<0.05). In the same group tissue and serum nitrate levels were decreased (p<0.05). Histopathologic analyses demonstrated typical morphologic changes characteristic of necrosis in I/R group. Melatonin attenuated ischemia-induced necrosis. Melatonin administration may significantly reduce the incidence of spinal cord injury following temporary aortic occlusion.

Reversal of long-term potentiation (LTP) by low-frequency stimulation (LFS) is often referred to as depotentiation (DP), a phenomenon that is time-dependent. The present study aimed to determine whether LTP could still be reversed when the stimulation was applied beyond the optimal time window in hippocampal slices from adult rats. Field excitatory postsynaptic potentials (fEPSPs) were recorded from the strata radiatum in CA1, following stimulation of Schaffer collaterals. Theta-burst stimulation (TBS) induced LTP that could be reversed by repeated paired-pulse LFS (PP-LFS) after almost 3 h post-TBS. Only when synapse strength reached a plateau did application of PP-LFS trigger DP. In addition, it was surprising to observe that PP-LFS, which generally induces LTD in adult rats, evoked an LTP-like further strengthening in previously potentiationed synapses, even in the presence of APV, a competitive antagonist of N-methyl- D-aspartate receptors (NMDA-Rs). Our results suggest that LTP can be reversed NMDAR-independently more than 2 h after TBS by PP-LFS in adult hippocampus and that saturation of LTP is effective to promote this process.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the Central Nervous System (CNS) of supposed autoimmune origin whose etiology still remains unknown. Epidemiological studies suggest that MS pathogenesis could be related to an infection superimposed on a predisposing genetic background. However, at present, no direct evidence for an infectious implication in MS autoimmunity exists. Recently, the potential role of Chlamydia pneumoniae as a causative agent of MS has received increasing attention. After the initial high rates reported for molecular and culture demonstration of C. pneumoniae in cerebrospinal fluid (CSF) of MS patients, the association between C. pneumoniae and MS was intensively investigated with controversial results. Seroepidemiological reports did not show any strong association between C. pneumoniae infection and the risk of MS. Isolation techniques failed to detect C. pneumoniae in CSF and brain tissue of MS patients. Polymerase chain reaction (PCR) evidence of C. pneumoniae in CSF and intrathecal synthesis of anti-C. pneumoniae IgG have been undetectable in MS patients or, if present, were not selectively associated with MS, but were shared by several inflammatory neurological conditions. Nevertheless, in a subgroup of MS patients, an association between PCR positivity for C. pneumoniae in CSF and disease activity was found. Intrathecal production of anti-C. pneumoniae high-affinity IgG predominated in MS progressive forms and metabolically active C. pneumoniae was identified in CSF. C. pneumoniae was recognized in CSF and brain tissue at immunohistochemical, molecular and ultrastructural levels. C. pneumoniae was also able to induce the animal model of MS. This growing body of data does not support a central role for C. pneumoniae as a candidate in MS pathogenesis, but suggests that, in a subset of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. Thus, the actual involvement of C. pneumoniae in MS still remains to be elucidated.

The blood brain barrier (BBB) plays an important role in the homeostatic regulation of the brain microenvironment and maintains the immune-privileged status of the brain by restricting the entry of T lymphocytes. Structurally, the BBB is formed by tight junctions between the endothelial cells. Astrocytes, pericytes and perivascular microglia surround the endothelial cells contributing to proper functioning of the BBB. Hypoxia, associated with disorders such as stroke, cardiac arrest, respiratory distress, carbon monoxide poisoning among many others, disrupts the BBB. Alterations in the endothelial cells such as increased pinocytotic vesicles and derangement of the tight junction proteins may be responsible for increased permeability at the BBB resulting in swelling of astrocyte end feet. The disruption of BBB in hypoxic conditions is multifactorial and may involve factors such as enhanced production of vascular endothelial growth factor (VEGF), nitric oxide (NO) and inflammatory cytokines. Although future research is needed to look into possible therapeutic strategies to improve the functioning of BBB in hypoxic conditions, experimental studies so far have reported beneficial effect of curcumin, melatonin, simvastatin and minocycline in ameliorating the increased BBB permeability in hypoxic conditions.