Antiamnestic effect of α7-nicotinic receptor agonist RJR-2403 in middle-aged ovariectomized rats with Alzheimer type dementia

Sapronov, N. S.; Fedotova, Yu. O.; Kuznetsova, N. N.

doi:10.1007/s10517-006-0455-y

Cited by 8 publications

(5 citation statements)

References 8 publications

(6 reference statements)

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“…Sapronov et al (Sapronov et al, 2006) reported that chronic treatment with a selective α4ß2-nicotinic receptor agonist in combination with E2 significantly improved performance in a rat model of Alzheimer’s-type dementia. This effect was blocked by mecamylamine, a nicotinic receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

Gibbs

Chipman

Hammond

et al. 2011

Hormones and Behavior

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We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer’s disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16–17 months of age. At 21–22 months of age rats began receiving daily injections of galanthamine (5 mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine + estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone were without significant effect. Effects were task-specific in that galanthamine + estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.

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Section: Discussionmentioning

confidence: 99%

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

Gibbs

Chipman

Hammond

et al. 2011

Hormones and Behavior

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“…Ovariectomized rats treated with 0.3 mg/Kg/d nicotine + E2 also performed better than other groups. Another study reported that chronic treatment with an α4β2-selective nAChR agonist in combination with E2 produced a pronounced anti-amnestic effect in a rat model of AD-type dementia (Sapronov et al, 2006). The effect was blocked by the nAChR antagonist mecamylamine.…”

Section: Discussionmentioning

confidence: 99%

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons

Gibbs

Chipman

Nelson

2011

Hormones and Behavior

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Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3 mg/Kg/day, i.p.) or vehicle, and then with 17β-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don+E2 significantly enhanced acquisition of the task in rats with partial lesions (<50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don+E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer’s disease.

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“…For in vivo activation of nAChRs, we used PNU-282987 (PNU), an α7-nAChR agonist, and RJR-2403 Oxalate (RJR), an α4β2-nAChR agonist. These agonists have a number of advantages that can be used to test our hypothesis; 1) they are blood-brain barrier (BBB) permeable 122-124, 142, 143 , 2) they do not require endogenous acetylcholine to stimulate receptors since they are direct agonists rather than positive allosteric modulators 122,123,142,[144][145][146][147] , and 3) repeated injection of these agonists is sufficient to show receptor activation in the rodent brains without causing receptor desensitization 145,146,[148][149][150] . PNU and RJR were prepared at concentrations of 1 mg/ml and intraperitoneally injected into 5-month-old 5XFAD and WT female and male mice at a dose of 5 mg/kg by themselves or together once per day for 7 days, a condition that is sufficient to stimulate each nAChR subtype in vivo [122][123][124]142 .…”

Section: In Vivo Activation Of Nachrsmentioning

confidence: 99%

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer’s disease

Lee,

Kim,

Kim

2024

Preprint

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Alzheimer’s disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons’ activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation and synaptic dysfunction in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction and fear memory loss in the amyloid pathology model mice. We thus suggest that co-activation of PV+ and SST+ cells is a novel strategy to reverse hippocampal dysfunction and cognitive decline in AD.

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Antiamnestic effect of α7-nicotinic receptor agonist RJR-2403 in middle-aged ovariectomized rats with Alzheimer type dementia

Cited by 8 publications

References 8 publications

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer’s disease

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