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Biomedical subjects

C M Hernandez

Publications and source records attributed to C M Hernandez.

9 recordsLinked to original sources
PubMed2005

Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats.

This study was designed to determine 1) whether repeated exposures to the acetylcholinesterase inhibitors (AChEIs) galantamine (GAL) or donepezil (DON) resulted in positive effects on nerve growth factor (NGF) and its receptors, cholinergic proteins, and cognitive function in the aged rat, and 2) whether GAL had any advantages over DON given its allosteric potentiating ligand (APL) activity at nicotinic acetylcholine receptors. Behavioral tests (i.e., water maze and light/dark box) were conducted in aged Fisher 344 rats during 15 days of repeated (subcutaneous) exposure to either GAL (3.0 or 6.0 mg/kg/day) or DON (0.375 or 0.75 mg/kg/day). Forty-eight hours after the last drug injection, cholinergic receptors were measured by [(125)I]-(+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([(125)I]IPH; epibatidine analog), (125)I-alpha-bungarotoxin ((125)I-BTX), [(3)H]pirenzepine ([(3)H]PRZ), and [(3)H]-5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate ([(3)H]AFDX-384, or [(3)H]AFX) autoradiography. Immunochemical methods were used to measure NGF, high (TrkA and phospho-TrkA)- and low (p75 neurotrophin receptor)-affinity NGF receptors, choline acetyltransferase (ChAT), and the vesicular acetylcholine transporter (VAChT) in memory-related brain regions. Depending on dose, both GAL and DON enhanced spatial learning (without affecting anxiety levels) and increased [(125)I]IPH, [(3)H]PRZ, and [(3)H]AFX (but decreased (125)I-BTX) binding in some cortical and hippocampal brain regions. Neither AChEI was associated with marked changes in NGF, NGF receptors, or VAChT, although DON did moderately increase ChAT in the basal forebrain and hippocampus. The results suggest that repeated exposures to either GAL or DON results in positive (and sustained) behavioral and cholinergic effects in the aged mammalian brain but that the APL activity of GAL may not afford any advantage over acetylcholinesterase inhibition alone.

Acetylcholinesterase↗
PubMed2005

Repeated nicotine exposure in rats: effects on memory function, cholinergic markers and nerve growth factor.

A decrease in the number of nicotinic-acetylcholine receptors (nAChRs) in the brain is thought to contribute to the cognitive dysfunction associated with diseases as diverse as Alzheimer's disease and schizophrenia. Interestingly, nicotine and similar compounds have been shown to enhance memory function and increase the expression of nAChRs and therefore, could have a therapeutic role in the aforementioned diseases. Nicotine has also been shown to exert positive effects on certain neurotrophins such as nerve growth factor (NGF), and therefore could play a role beyond mere symptomatic therapy. However, to date, comprehensive studies of nicotine's effects on the expression of specific acetylcholine (ACh) receptor subtypes, key cholinergic proteins (that are regulated by NGF) such as choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT) are lacking. Studies to further investigate the effects of nicotine on NGF especially its high- and low-affinity receptors are also needed. In the present study, male Wistar rats exposed a relatively low dosage of nicotine (0.35 mg/kg every 12 h) for 14 days demonstrated improved memory performance (assessed in two separate water maze testing methods) when compared with controls. Autoradiographic experiments indicated that nicotine increased [3H]-epibatidine, [125I]-alpha-bungarotoxin and [3H]-AFDX384, but not [3H]-pirenzepine binding sites in several learning- and memory-related brain areas. The expression of ChAT, VAChT, as well as tropomyosin-receptor kinase A (TrkA) NGF receptors and phospho-TrK receptors was increased by nicotine in the hippocampus. No changes were observed in the levels of the NGF peptide or low affinity p75 neurotrophin receptors (p75NTR), however. These results suggest that repeated exposure to nicotine results in positive effects on central cholinergic markers and memory function, which may be mediated via effects on high-affinity NGF receptors.

Acetylcholine↗
PubMed2001

Dahl salt-sensitive and salt-resistant rats: examination of learning and memory performance, blood pressure, and the expression of central nicotinic acetylcholine receptors.

Substantial human and animal data suggest a correlation between hypertension and memory impairment that may appear prior to overt manifestations of cerebrovascular pathology. It is unclear, however, whether hypertension plays a causal role in these memory deficits, whether hypertension and cognitive impairment are each based in family history and not interdependent, or whether a combination of these factors is important. The purpose of this study was to assess whether deficits in memory performance and nicotinic acetylcholine receptors were present in Dahl salt-sensitive rats (as observed previously in spontaneously hypertensive rats) and whether the presence of hypertension per se (induced with an 8% Na(+) diet) contributed to the deficits. Memory was assessed in a passive avoidance task, an eight-arm radial arm maze and in a water maze task, and nicotinic receptors were measured via quantitative receptor autoradiography utilizing [125I]alpha-bungarotoxin and [3H]epibatidine. Salt-sensitive rats exhibited impaired performance in both spatial learning tasks, but not the passive avoidance task, compared to controls (salt-resistant strain) and they exhibited reductions in nicotinic receptors labeled by [125I]alpha-bungarotoxin but not [3H]epibatidine in some brain regions, including some areas important for memory (e.g. the hippocampus and amygdala). In the radial arm maze, the degree of memory impairment and in binding studies the reduced expression of nicotinic receptors each failed to correlate with the highest blood pressures, and the salt-sensitive animals were impaired relative to controls whether or not the high Na(+) diet was administered. In contrast, higher blood pressures did correlate with inferior task performance in the water maze. These findings may suggest that the genetics of the subjects were critical for performance when appetitive drives were involved, but diet (and perhaps hypertension) were key to performance when memory did not involve appetitive drives or mechanisms. Overall, the data obtained from Dahl rats appear to support the role of family history (selective breeding in rats) as underlying the reductions in central nicotinic acetylcholine receptors, whereas both family history and hypertension may contribute to poor cognitive performance.

Animals↗
PubMed2000

Deficits in spatial learning and nicotinic-acetylcholine receptors in older, spontaneously hypertensive rats.

Spontaneously hypertensive rats are often used as models of attention deficit hyperactivity disorder and to investigate the effects of hypertension on cognitive function. Along with the wide variety of cardiovascular anomalies, these animals as young adults also exhibit deficits in memory and attention and central nicotinic-acetylcholine receptor sites. These findings may have particular significance since nicotinic receptors appear to be involved in the regulation of cerebral circulation and mnemonic function. Furthermore, a lack of high affinity nicotinic receptors (in knockout mice) has also been shown to accelerate both the structural and cognitive degeneration associated with age, findings that may be especially relevant to age-related memory disorders such as Alzheimer's Disease where large deficits in nicotinic receptors are observed. Since spontaneously hypertensive rats appear to be both memory-impaired and deficient in nicotinic receptors at a young age (compared to the non-hypertensive phenotype, Wistar-Kyoto rats), we were interested to learn if these conditions were exacerbated in older animals with particular interest in specific nicotinic receptor subtypes in memory areas of the brain. Spatial learning was assessed in 15-month-old subjects of each phenotype (i.e. hypertensive and non-hypertensive) using a two-phase water maze paradigm, and nicotinic receptors were measured via autoradiography with [125I]-alpha-bungarotoxin and [3H]-epibatidine. In the water maze, both groups learned to locate a hidden platform as indicated by progressively shorter latencies across training days, however, Wistar-Kyoto rats were more efficient in both phases. While the number of both bungarotoxin and epibatidine binding sites was lower in the hypertensive rats across several brain regions, in the case of epibatidine binding, the magnitude of the difference and the number of areas affected was generally greater and included areas important for spatial learning (e.g. frontal and entorhinal cortex). In a direct comparison between 3-month-old and 15-month-old rats of each phenotype, epibatidine sites were markedly reduced by age (i.e. by greater than 50% in some cases) across multiple brain regions in both groups, although Wistar-Kyoto rats appeared to be more substantially affected by age. These data further support the use of the spontaneously hypertensive rat as model for studying learning-impairment and reduced central nicotinic receptors and also indicate that these characteristics persist and (in the case of high affinity nicotinic receptor cites) worsen with age.

Acetylcholine↗
PubMed1999

The neuroprotective effects of non-NMDA antagonists in the cerebellum of the spastic Han Wistar mutant.

Excitotoxicity resulting from the dysfunction of glutamate receptors has been attributed to neurodegeneration seen in many brain disorders. In our laboratory, the spastic Han Wistar mutant is currently utilized as a potential model of excitotoxicity. The mutant is characterized by progressive neuronal degeneration, hindlimb paresis and ataxia which culminates in the animal's death at approximately 65 days of age. In this study, neuroprotection derived from acute administration of the non-NMDA antagonist GYKI 52466, and chronic administration of the non-NMDA antagonist CNQX was examined in order to determine the potential roles of non-NMDA receptors in the observed neurodegeneration. Mutants injected with GYKI 52466 (15 mg/kg), twice a week for 3 weeks, exhibited increased life spans (14%) and extended motor activity than their vehicle-treated mutant siblings. In a separate group of mutants, CNQX (either 50 or 500 microM) was infused directly into the third ventricle of the mutant's brain utilizing osmotic pumps. A statistically significant increase in motor activity (22%) was detected for mutants treated with a dose of 50 microM CNQX compared to their vehicle-treated siblings. Finally, cerebellar histological evaluations of mutants treated with both 50 and 500 microM CNQX showed dose-dependent higher cerebellar Purkinje cell counts. These findings suggest that non-NMDA receptors play a significant role in neurodegeneration in this animal.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1976

Nefopam hydrochloride: new analgesic agent.

Two dose-levels of nefopam hydrochloride (i.e. 30 mg and 60 mg) were compared with two dose-levels of aspirin (i.e. 300 mg and 600 mg) and placebo in 125 male patients having pain associated with muscle disorders. Drugs were given as a single dose and pain intensity and side-effects monitored at thirty minutes and then hourly for four hours. Time-course action of the drugs revealed that aspirin 300 mg failed to achieve statistically significant analgesia at any post-treatment observation, whereas nefopam 60 mg was significantly better than placebo (p less than 0-05) at one and three hours in terms of pain intensity and at one hour in terms of pain intensity difference scores. Aspirin 600 mg was significantly different from placebo (p less than 0-05) at all hourly observations for both efficacy parameters, as was nefopam 30 mg (p less than 0-01). Summation of pain intensity difference scores showed aspirin 600 mg and nefopam 30 mg to be significantly different from placebo at the 0.025 and 0.005 levels respectively.

Analgesics↗