Vascular changes in the spinal cord in N-methyl-d-aspartate-induced excitotoxicity: morphological and permeability studies

Nag, S.

doi:10.1007/bf00304465

Cited by 24 publications

(15 citation statements)

References 23 publications

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“…Therefore, it is reasonable to suggest that the NMDA receptor population of neurons may also have a role in MS and EAE. In support of our suggestions, intraventricular, intrathecal, and intrastriatal administration of NMDA to rats has led to the induction of BBB permeability, which is intrinsic to the pathology of MS and EAE (Dietrich et al, 1992;Nag, 1992;Miller et al, 1996). Importantly, the neuronal ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor has recently been closely linked with neuronal loss and oligodendrocyte depletion during EAE (Pitt et al, 2000;Smith et al, 2000).…”

Section: Discussionsupporting

confidence: 68%

Modulation of Blood-Brain Barrier Dysfunction and Neurological Deficits during Acute Experimental Allergic Encephalomyelitis by theN-Methyl-d-aspartate Receptor Antagonist Memantine

Paul

Bolton²

2002

J Pharmacol Exp Ther

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Previous studies by us have strongly indicated a role for the N-methyl-D-aspartate (NMDA) receptor in the pathogenesis of experimental allergic encephalomyelitis (EAE) and, moreover, the loss of blood-brain barrier (BBB) integrity implicit in the disease. The current investigation has used the NMDA receptor antagonist memantine to modify the neurological course of EAE and, in particular, prevent BBB breakdown. Memantine was administered orally either semiprophylactically, from day 7 postinoculation (PI), or therapeutically, 10 to 11 days PI. Semiprophylactic administration of drug at 60 mg/kg b.wt. significantly restored BBB integrity, reduced symptoms, and limited inflammatory lesions (p Ͻ 0.05), when assessed 12 days PI. Higher concentrations of memantine did not notably advance disease improvements observed at 60 mg/kg b.wt., and 40-mg/kg b.wt. doses only reduced histological scores (p Ͻ 0.05).Therapeutic application of memantine was found to be as effective as semiprophylactic dosing. Administration of drug at 60 mg/kg b.wt. was demonstrated as the optimum dose, significantly reducing disease, BBB permeability, and lesions (p Ͻ 0.01). Extended studies revealed that, after cessation of memantine treatment using either dosing regime, any subsequent appearance of disease was suppressed in severity and duration. We have provided further strong evidence in support of a role for the NMDA receptor in the development of EAE and, in particular, the loss of BBB function and recruitment of inflammatory cells. Moreover, memantine is therapeutically efficacious, suggesting the NMDA receptor as a viable pharmacological target for future treatment of human neurological conditions such as multiple sclerosis.

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Section: Discussionsupporting

confidence: 68%

Modulation of Blood-Brain Barrier Dysfunction and Neurological Deficits during Acute Experimental Allergic Encephalomyelitis by theN-Methyl-d-aspartate Receptor Antagonist Memantine

Paul

Bolton²

2002

J Pharmacol Exp Ther

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“…In addition, confluent deposits of HRP were observed in abluminal caveolae and the adjacent endothelial basement membranes, which did not otherwise contain tracer ( > Figure 3-4b), suggesting that caveolae were depositing HRP in the endothelial basement membrane and the direction of caveolar passage was from the vascular lumen to the subendothelium. This finding was observed in all subsequent studies of experimental hypertension (Nag et al, 1980;Nag, 1984aNag, , 1986Nag and Harik, 1987) and in other models such as spinal cord injury (Beggs and Waggener, 1976), seizures (Hedley-Whyte et al, 1977), bradykinin-induced BBB breakdown (Raymond et al, 1986), and excitotoxic brain damage (Nag, 1992). The active participation of caveolae in transfer of proteins, such as HRP across cerebral endothelium is supported by the absence of such transport in vessels fixed for 45 min before the perfusion of peroxidase .…”

Section: Direction Of Caveolar Passage In Endotheliummentioning

confidence: 73%

“…Multifocal areas of HRP extravasation around cerebral vessels were observed in diverse models, such as hypertension (Nag, 1998); spinal cord injury (Beggs and Waggener, 1976); seizures (Hedley-Whyte et al, 1977;Westergaard, 1980;Nitsch et al, 1986); experimental autoimmune encephalomyelitis (Claudio et al, 1989); excitotoxic brain damage (Nag, 1992); brain trauma (Povlishock et al, 1978), brain tumors ; and BBB breakdown induced by bradykinin (Raymond et al, 1986;Hashizume and Black, 2002), histamine (Dux and Joo, 1982), and leukotriene C4 (Hashizume and Black, 2002), and other models as reviewed previously (Nag, 2003b;Lossinsky and Shivers, 2004). In these studies, HRP was present in all layers of the vessel wall and extended into the gap junctions between astrocytic foot processes and into the adjacent extracellular spaces.…”

Section: Enhanced Transcytosismentioning

confidence: 97%

Structure and Pathology of the Blood–Brain Barrier

Nag¹

2007

Handbook of Neurochemistry and Molecular Neurobiology

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“…However, this BBB dysfunction is likely secondary to neurotoxicity. Nag (32) found that BBB breakdown in the spinal cord always followed the excitotoxic neuronal lesion after intrathecal NMDA infusion.…”

Section: Discussionmentioning

confidence: 99%

Cerebromicrovascular endothelial cells are resistant to l-glutamate

Domoki

Kis

Gáspár

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Cerebral microvascular endothelial cells (CMVECs) have recently been implicated as targets of excitotoxic injury by L-glutamate (L-glut) or N-methyl-Daspartate (NMDA) in vitro. However, high levels of L-glut do not compromise the function of the blood-brain barrier in vivo. We sought to determine whether primary cultures of rat and piglet CMVECs or cerebral microvascular pericytes (CMVPCs) are indeed sensitive to L-glut or NMDA. Viability was unaffected by 8-h exposure to 1-10 mM L-glut or NMDA in CMVECs or CMVPCs isolated from both species. Furthermore, neither 1 mM L-glut nor NMDA augmented cell death induced by 12-h oxygen-glucose deprivation in rat CMVECs or by 8-h medium withdrawal in CMVPCs. Additionally, transendothelial electrical resistance of rat CMVEC-astrocyte cocultures or piglet CMVEC cultures were not compromised by up to 24-h exposure to 1 mM L-glut or NMDA. The Ca 2ϩ ionophore calcimycin (5 M), but not L-glut (1 mM), increased intracellular Ca 2ϩ levels in rat CMVECs and CMVPCs assessed with fluo-4 AM fluorescence and confocal microscopy. CMVEC-dependent pial arteriolar vasodilation to hypercapnia and bradykinin was unaffected by intracarotid infusion of L-glut in anesthetized piglets by closed cranial window/intravital microscopy. We conclude that cerebral microvascular cells are insensitive and resistant to glutamatergic stimuli in accordance with their in vivo role as regulators of potentially neurotoxic amino acids across the blood-brain barrier.N-methyl-D-aspartate; blood-brain barrier; cerebrovascular reactivity; glutamate excitotoxicity; intracellular calcium L-GLUTAMATE (L-glut) is one of the most important excitatory amino acids in the central nervous system. Apart from its well-known neurotransmitter role, L-glut plays a critical role in ammonia removal from the brain. L-Glut transported from the blood plasma takes up ammonia and leaves as L-glutamine (12). This balanced L-glutamate/L-glutamine countertransport is regulated by cerebral microvascular endothelial cells (CMVECs) forming the blood-brain barrier (BBB). Furthermore, CMVECs can pump L-glut from the brain to the blood, and thus they provide a functional interface for the regulated bidirectional transport of L-glut (18, 39). Human blood plasma L-glut levels range between 20 and 200 M, and they may exceed 700 M after ingestion of high amounts of L-glut under experimental conditions (4, 41). These plasma L-glut concentrations are not neurotoxic in vivo, although these levels are excitotoxic to neurons in vitro, suggesting that CMVECs are resistant to high L-glut levels and prevent the passive transport of L-glut into the brain.Surprisingly, several recent reports have proposed that the L-glut levels that occur during cerebral ischemia can injure or kill CMVECs via excitotoxic mechanisms in vitro. CMVECs have been reported to possess various L-glut receptor subunits or L-glut binding sites in rat, piglet, or human CMVECs (1,5,27,34,36,45). High concentrations of L-glut (1-3 mM), at least in vitro, are claimed to result in N-met...

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Vascular changes in the spinal cord in N-methyl-d-aspartate-induced excitotoxicity: morphological and permeability studies

Cited by 24 publications

References 23 publications

Modulation of Blood-Brain Barrier Dysfunction and Neurological Deficits during Acute Experimental Allergic Encephalomyelitis by theN-Methyl-d-aspartate Receptor Antagonist Memantine

Modulation of Blood-Brain Barrier Dysfunction and Neurological Deficits during Acute Experimental Allergic Encephalomyelitis by theN-Methyl-d-aspartate Receptor Antagonist Memantine

Structure and Pathology of the Blood–Brain Barrier

Cerebromicrovascular endothelial cells are resistant to l-glutamate

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