Impaired Learning and Abnormal Open‐field Behaviours of Rats After Early Postnatal Anoxia and the Beneficial Effect of the Calcium Antagonist Nimodipine

Nyakas, C.; Markel, E; Schuurman, T.; Luiten, P.G.M.

doi:10.1111/j.1460-9568.1991.tb00077.x

Cited by 45 publications

(18 citation statements)

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“…These functional deficits were associated with decreased staining for neurofilament immunoreactivity, astrocytes (GFAP), and oligodendrocytes (RIP) in the hippocampus and somatosensory and motor cortices in the younger animals and only minimal changes in these regions upon reaching adulthood (30). Similar findings have been reported using other hypoxic paradigms during early postnatal life (31)(32)(33). For example, Nyakas and colleagues (34) have conclusively demonstrated that application of hypoxia or hypoxic-like treatments leads to substantial effects in the architectural development of specific neural regions (e.g.…”

Section: Discussionsupporting

confidence: 73%

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

et al. 2005

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Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10-and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits. OSA is a highly prevalent condition that affects 2-3% of all children (1-3). It is characterized by the repetitive development of either complete or partial upper airway occlusion that leads to periodic hypoxemia and hypercapnia and to recurring arousals. In recent years, it has become apparent that OSA imposes substantial neurobehavioral morbidity (4 -6), particularly of functions pertaining to the PFC (7), and that such alterations in attention, executive, and intellectual function may not be completely reversible (8). The recent development of a rodent model, whereby IH is applied during sleep, has allowed for improved delineation of some of the potential mechanisms underlying the morbid consequences of OSA (8 -17). Furthermore, a unique period of neuronal susceptibility emerged, such that developing rats exposed to IH displayed reduced apoptosis during the immediate postnatal period but markedly enhanced neuronal cell loss between 10 and 25 d of age, compared with adult animals (18). Furthermore, exposure to IH during this period was associated with marked reductions in the ability to acquire a spatial task in the water maze and with locomotor hyperactivity in males but not in females (9). The potential irreversibility of the IH-induced effects was further suggested by Decker and colleagues (19), who reported altered dopaminergic transmission in rats exposed perinatally

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Section: Discussionsupporting

confidence: 73%

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

et al. 2005

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“…These results are in accordance with previous data showing the ability of nimodipine to improve learning in either aged or hypertensive animals. [12][13][14][15][16][17][18][19] Notwithstanding, the present data from middle-aged normotensive WKY and SHR may further suggest that the presence of aging and hypertension produces additive cognitive alterations 2 that can be partially reversed by nimodipine. …”

Section: )mentioning

confidence: 88%

“…Because nimodipine was not altered by exposure to the body temperature during 4 weeks, 3 the behavioral and cardiovascular changes observed in the present study are due to drug treatment. With use of the multiple variable interval extinction test in 3-month-old SHR, but not in WKY of the same age, an improving effect of nimodipine on learning was detected 18,19 ; this lack of effect in WKY could have been due to the age of the animals (3 months). In fact, we found that 3-month-old but not middleaged (12-month-old) WKY display full ability to learn.…”

Section: Nimodipine Reverses Cognitive Deficitsmentioning

confidence: 92%

“…3 This possibility is supported by previous studies showing that nimodipine, given at doses and routes of administration causing no hypotensive effects, has clear beneficial effects on learning. 12,13,[15][16][17][18][19]39 Although several routes have been tested for repeated administration of nimodipine, 12,[15][16][17][18][19] the continuous infusion with osmotic minipumps was selected because it provides a sustained and stable administration of low (light-protected) doses of the drug. Indeed, our administration protocol was designed to test a possible direct effect of nimodipine on learning unrelated to its hypotensive effects, thus avoiding drastic and long-lasting changes in blood pressure and to approximating a slowrelease oral dose for humans.…”

Section: Nimodipine Reverses Cognitive Deficitsmentioning

confidence: 99%

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Spontaneously Hypertensive Rats

Meneses

Hong

1998

Hypertension

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Abstract-Spontaneously hypertensive rats (SHR) of 3 to 12 months of age learned and retrieved less information than normotensive Wistar-Kyoto rats (WKY), although no difference was found with animals from 18 and 24 months of age. The combined influence of hypertension and aging had an additive detrimental effect on cognitive functions. Notwithstanding these deficiencies in learning and memory, SHR have seldom been used as a model in the screening of drugs with therapeutic potential for treatment of disorders of cognitive processes. Moreover, the calcium channel blocker nimodipine has beneficial effects on learning in both aged and hypertensive animals and humans. However, no attempt has been made to investigate whether nimodipine can reverse the additive deleterious effects of aging and hypertension in the same subject. We recently reported that deteriorated animals (middle-aged and/or hypertensive) chronically treated with nimodipine (via osmotic minipumps) exhibit higher learning scores. This information indicates that nimodipine can reverse the impairing effects of either aging or hypertension on learning; the presence of the two conditions, however, produces a severe impairment that can be partially reversed by this drug. Therefore, we propose that mature and middle-aged SHR represent a model for the screening of potentially useful drugs in the treatment of learning disorders, probably associated with hypertension and/or aging. Nevertheless, it must be remembered that the SHR is a genetic model and the appearance of neural disturbances could be a parallel genetic phenomenon and not necessarily or exclusively related to hypertension per se. (Hypertension. 1998;31:968-972.)Key Words: rats, inbred SHR Ⅲ learning Ⅲ memory Ⅲ aging Ⅲ pharmacology Ⅲ models A great expansion of experimental research began with the development of rat strains with genetically inherited hypertension. The SHR offers specific and uniform genetic predisposition, 1 thus allowing the study of the causes, mechanisms, and pathology of hypertension, as well as its behavioral consequences, and the comparison of the efficacy of proposed therapeutic interventions in relation to existing clinical treatments. Moreover, central neurohormonal mechanisms constitute the dominating trigger influence in SHR 1 and provide a model of hypertension that allows the study of the combined influence of both aging and hypertension on cognitive and physical functions on different developmental stages.2,3 Notwithstanding, the SHR is a genetic model, and the appearance of neural disturbances could be a parallel genetic phenomenon and not necessarily or exclusively related to the elevated blood pressure per se. Normal aging also produces a slow decline in neuron population, tissue distensibility, basal metabolic rate, and oxygen consumption, thus affecting cardiovascular performance. The aim of the present work was to present evidence obtained in our laboratory supporting the idea that the SHR is a suitable behavioral model to test drugs with potential therapeutic us...

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“…Seventy-two hours postsurgery, the behavior of the animals was assessed in a light-independent small open-field paradigm (Nyakas et al, 1991). Animals were placed into individual Perspex arenas, 24 ϫ 24 cm in diameter with 30-cm high transparent walls, for 25 min.…”

Section: Behavioral Testingmentioning

confidence: 99%

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

Nimmrich¹,

Szabo²,

Nyakas³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is thought to underlie a variety of neurological disorders, and inhibition of either the NMDA receptor itself, or molecules of the intracellular cascade, may attenuate neurodegeneration in these diseases. Calpain, a calcium-dependent cysteine protease, has been identified as part of such an NMDA receptorinduced excitotoxic signaling pathway. The present study addressed the question of whether inhibition of calpain can prevent neuronal cell death and associated behavioral deficits in a disease-relevant animal model, which is based on excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. Excitotoxic lesions of the nucleus basalis with NMDA induced a markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor,, dose-dependently prevented the behavioral deficit. Subsequent analysis of choline acetyltransferase in the cortical mantle of the lesioned animals revealed that application of A-705253 dose-dependently and significantly attenuated cholinergic neurodegeneration. Calpain inhibition also significantly diminished the accompanying gliosis, as determined by immunohistochemical analysis of microglia activation. Finally, inhibition of calpain by A-705253 and the peptidic calpain inhibitor N-acetyl-Leu-LeuNle-CHO did not impair long-term potentiation in hippocampal slices, indicating that calpain inhibition interrupts NMDA excitotoxicity pathways without interfering with NMDA receptormediated signaling involved in cognition. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of excitotoxicity-induced neuronal decline without interfering with the physiological neuronal functions associated with learning and memory processes. Thus, calpain inhibition may be a promising and novel approach for the treatment of various neurodegenerative disorders.Calpains in the central nervous system are Ca 2ϩ -dependent cysteine proteases, which can modulate the conformation, localization, and activity of various proteins. Calpaininduced modifications have a profound affect on biological processes as different as cell cycle progression and vesicular trafficking. They are an integrative part of several signaling cascades, but they can also contribute to apoptotic and necrotic cell death in pathological conditions. For this reason, calpains have been discussed extensively as target for therapeutic interventions in a number of neurodegenerative disease that are associated with neuronal loss (for review, see Huang and Wang, 2001;Goll et al., 2003;Zatz and Starling, 2005).In that respect, it has recently been shown that inhibition of calpains prevents excitotoxic neuronal cell death in vitro (Caba et al., 2002;Ray et al., 2006) and in vivo (Chiu et al., 2005;Takano et al., 2005). Excitotoxicity is caused by an overstimulation of N-methyl-D-aspartate (NMDA) receptors, and there is now growing evidence that calpain cleaves sevArticle, publication date, and cita...

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Impaired Learning and Abnormal Open‐field Behaviours of Rats After Early Postnatal Anoxia and the Beneficial Effect of the Calcium Antagonist Nimodipine

Cited by 45 publications

References 37 publications

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

Spontaneously Hypertensive Rats

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

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