A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. OBJECTIVE: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. METHODS: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. RESULTS: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. CONCLUSION: DA4-JC is a promising drug for the treatment of AD.

DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP/PKA/CREB Signaling Pathways.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. OBJECTIVE: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. METHODS: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aß plaques and neuroinflammation in the brain. IL-1ß, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. RESULTS: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aß deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1ß and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. CONCLUSION: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

A GLP-1/GIP/Gcg receptor triagonist improves memory behavior, as well as synaptic transmission, neuronal excitability and Ca2+ homeostasis in 3xTg-AD mice.

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health and cannot be stopped by current treatments. Type 2 diabetes mellitus (T2DM) is a risk factor for AD. Our recent studies reported the neuroprotective effects of a GLP-1/GIP/Glucagon receptor triagonist (Triagonist), a novel unimolecular anti-diabetic drug, in cognitive and pathological improvements of 3xTg-AD mice. However, the detailed electrophysiological and molecular mechanisms underlying neuroprotection remain unexplored. The present study investigated the underlying electrophysiological and molecular mechanisms further by using whole-cell patch clamp techniques. Our results revealed that chronic Triagonist treatment effectively reduced working memory and reference memory errors of 3xTg-AD mice in a radial maze test. In addition, the Triagonist increased spontaneous excitatory synaptic activities, differentially modulated voltage- and chemically-gated Ca2+ flux, and reduced the over-excitation of pyramidal neurons in hippocampal slices of 3xTg-AD mice. In addition, chronic Triagonist treatment also up-regulated the expression levels of synaptophysin and PSD-95 in the hippocampus of 3xTg-AD mice. These results indicate that the Triagonist could improve memory formation, as well as synaptic transmission, Ca2+ balance, and neuronal excitability in 3xTg-AD mice. These neuroprotective effects of Triagonist may be involved in the up-regulation of synaptophysin and PSD-95. Therefore, the study suggests that multi-receptor agonists might be a novel therapeutic strategy for the treatment of AD.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3ß in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.

A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-ß (Aß) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p-CREB, T286 p-CAMKII and S9 p-GSK3ß in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

[GLP-1/GIP/Gcg receptor Triagonist improves the cognitive behaviors in triple-transgenic mice of Alzheimer's disease].

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP. Recently, the Triagonist has been reported to be effective in alleviating diabetic complications in rodent models of obesity. The present study observed for the first time the cognitive improvement effects of the Triagonist in the triple-transgenic AD mice (3xTg-AD) by using multiple behavioral techniques, and explored its probable molecular mechanisms using ELISA and Western blot. The results showed that the chronic treatment with the Triagonist (i.p.) significantly reversed the impairments in working memory of 3xTg-AD mice, with an obvious increase in the percentage of correct spontaneous alternation in the Y maze; the Triagonist treatment also improved long-term spatial memory and re-learning ability of 3xTg-AD mice in classical Morris water maze and reverse water maze tests, with decreased escape latency in under water platform tests and increased swimming time in probe tests. ELISA and Western blot experiments showed that the Triagonist up-regulated the levels of cAMP, PKA and p-CREB in the hippocampus of 3xTg-AD mice. These results indicate that GLP-1/GIP/Gcg receptor Triagonist can improve the cognitive behaviors in 3xTg-AD mice, and the up-regulation of hippocampal cAMP/PKA/CREB signal pathway may mediate the neuroprotection of the Triagonist, suggesting that the GLP-1/GIP/Gcg receptor Triagonist may be a novel therapeutic strategy for the treatment of AD.

Davunetide improves spatial learning and memory in Alzheimer's disease-associated rats.

Memory loss and cognition decline are the main clinical manifestations of Alzheimer's disease (AD). Amyloid ß protein (Aß) aggregated in the brain is one of the key pathological characteristics of AD and responsible for the deficits in learning and memory. It is reported that davunetide, an octapeptide derived from activity-dependent neuroprotective protein (ADNP), inhibited Aß aggregation and Aß-induced neurotoxicity. To further characterize the neuroprotective roles of davunetide and its possible mechanism, the present study investigated the effects of davunetide on Aß1-42-induced impairments in spatial memory, synaptic plasticity and hippocampal AKT level. In Morris water maze (MWM) test, bilateral intrahippocampal injection of Aß1-42 significantly increased escape latency and decreased target quadrant swimming time of rats, while three weeks of intranasal application of davunetide reversed the Aß1-42-induced learning deficits and memory loss in a dose-dependent manner. In vivo field potentiation recording showed that Aß1-42 suppressed long-term potentiation (LTP) of excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 region of rats, while davunetide effectively blocked the suppression of LTP, without affecting paired-pulse facilitation (PPF). Western blotting experiments showed a significant decrease in the level of hippocampal p-AKT (Ser473), not total AKT, in Aß1-42 only group, which was mostly antagonized by davunetide treatment. These findings demonstrate that davunetide, probably by enhancing PI3K/AKT pathway, plays an important positive role in attenuating Aß1-42-induced impairments in spatial memory and synaptic plasticity, suggesting that davunetide could be an effective therapeutic candidate for the prevention and treatment of neurodegenerative disease such as AD.

GLP-1 analogue CJC-1131 prevents amyloid ß protein-induced impirments of spatial memory and synaptic plasticity in rats.

Although amyloid ß protein (Aß) has been recognized as one of the main pathological characteristics in the brain of Alzheimer's disease (AD), the effective strategies against Aß neurotoxicity are still deficient up to now. Glucagon-like peptide 1 (GLP-1), a natural gut hormone, was found to be effective in modulating insulin signaling and neural protection, but short half-life limited its clinical application in AD treatment. CJC-1131, a newly designed GLP-1 analogue with very longer half-life, has shown good effectiveness in the treatment of type 2 diabetes mellitus (T2DM). However, it is unclear whether CJC-1131 could alleviate Aß-induced neurotoxicity in cognitive behavior and electrophysiological property. The present study investigated the effects of CJC-1131 on the Aß-induced impairments in spatial memory and synaptic plasticity of rats by using Morris water maze test and in vivo field potential recording. The results showed that Aß1-42-induced increase in the escape latency of rats in hidden platform test and decrease in swimming time percent in target quadrant were effectively reversed by CJC-1131 pretreatment. Further, CJC-1131 prevented against Aß1-42-induced suppression of hippocampal long term potentiation (LTP). In addition, Aß1-42 injection resulted in a significant decrease of p-PKA in the hippocampus, which was effectively prevented by CJC-1131 treatment. These results indicated that CJC-1131 protected the cognitive function and synaptic plasticity of rats against Aß-induced impairments, suggesting that GLP-1 analogue CJC-1131 might be potentially beneficial to the prevention and treatment of AD, especially those with T2DM or blood glucose abnormality.

Lixisenatide attenuates the detrimental effects of amyloid ß protein on spatial working memory and hippocampal neurons in rats.

Type 2 diabetes mellitus(T2DM) is a risk factor of Alzheimer's disease (AD), which is most likely linked to impairments of insulin signaling in the brain. Hence, drugs enhancing insulin signaling may have therapeutic potential for AD. Lixisenatide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analogue, facilitates insulin signaling and has neuroprotective properties. We previously reported the protective effects of lixisenatide on memory formation and synaptic plasticity. Here, we describe additional key neuroprotective properties of lixisenatide and its possible molecular and cellular mechanisms against AD-related impairments in rats. The results show that lixisenatide effectively alleviated amyloid ß protein (Aß) 25-35-induced working memory impairment, reversed Aß25-35-triggered cytotoxicity on hippocampal cell cultures, and prevented against Aß25-35-induced suppression of the Akt-MEK1/2 signaling pathway. Lixisenatide also reduced the Aß25-35 acute application induced intracellular calcium overload, which was abolished by U0126, a specific MEK1/2 inhibitor. These results further confirmed the neuroprotective and cytoprotective action of lixisenatide against Aß-induced impairments, suggesting that the protective effects of lixisenatide may involve the activation of the Akt-MEK1/2 signaling pathway and the regulation of intracellular calcium homeostasis.

Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-ß peptide-induced impairment of spatial learning and memory in rats.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aß) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aß1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aß1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aß1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aß1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD.

Colivelin ameliorates amyloid ß peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats.

Amyloid ß peptide (Aß) has been thought to be neurotoxic and responsible for the impairment of learning and memory in Alzheimer's disease (AD). Humanin (HN), a 24 amino acid polypeptide first identified from the unaffected occipital lobe of an AD patient, is believed to be neuroprotective against the AD-related neurotoxicity. In this study, we investigated the neuroprotective effects of Colivelin (CLN), a novel HN derivative, against Aß by using behavioral test, in vivo electrophysiological recording, and intracellular calcium imaging. Our results showed that intrahippocampal injection of CLN (0.2 nmol) effectively prevented Aß25-35 (4 nmol)-induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Aß25-35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Aß25-35-induced calcium overload in primary cultured hippocampal neurons. These results indicate that CLN has significant neuroprotective properties against Aß, and CLN may holds great promise for the treatment and prevention of AD.

Liraglutide protects against amyloid-ß protein-induced impairment of spatial learning and memory in rats.

Type 2 diabetes mellitus is a risk factor of Alzheimer's disease (AD), most likely linked to an impairment of insulin signaling in the brain. Liraglutide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analog, facilitates insulin signaling and shows neuroprotective properties. In the present study, we analyzed the effects of liraglutide on the impairment of learning and memory formation induced by amyloid-ß protein (Aß), and the probable underlying electrophysiological and molecular mechanisms. We found that (1) bilateral intrahippocampal injection of Aß(25-35) resulted in a significant decline of spatial learning and memory of rats in water maze tests, together with a serious depression of in vivo hippocampal late-phase long-term potentiation (L-LTP) in CA1 region of rats; (2) pretreatment with liraglutide effectively and dose-dependently protected against the Aß(25-35)-induced impairment of spatial memory and deficit of L-LTP; (3) liraglutide injection also activated cAMP signal pathway in the brain, with a nearly doubled increase in the cAMP contents compared with control. These results strongly suggest that upregulation of GLP-1 signaling in the brain, such as application of liraglutide, may be a novel and promising strategy to ameliorate the learning and memory impairment seen in AD.

Amyloid ß-protein suppressed nicotinic acetylcholine receptor-mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons.

Amyloid ß protein (Aß) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Aß and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aß-induced damage of nAChRs. This study investigated the effects of Aß fragments on nAChR-mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole-cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4ß2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM-µM) of Aß25-35, Aß31-35, or Aß35-31 alone did not trigger any membrane current, but pretreatment with 1 µM Aß25-35 and Aß31-35 similarly and reversibly suppressed the nicotine-induced currents; (3) further, choline- and epibatidine-induced currents were also reversibly suppressed by the Aß pretreatment, but more prominent for the choline-induced response. These results demonstrate that the functional activity of both α7 and α4ß2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aß treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aß in AD. In addition, the similar suppression of nAChR currents by Aß25-35 and Aß31-35 suggests that the sequence 31-35 in Aß molecule may be a shorter active center responsible for the neurotoxicity of Aß in AD.

[[Gly14]-humanin protects against Aß31₋35-induced impairment of spatial learning and memory in rats].

Amyloid ß protein (Aß) is closely involved in the pathogenesis of Alzheimer's disease (AD), and one of the main strategies for AD treatment is antagonizing the neurotoxicity of Aß or even clearing the Aß deposited in the brain. The present study was aimed to observe the effects of intrahippocampal injection of Aß31₋35 on the spatial learning and memory of rats by using Morris water maze technique, and explore the neuroprotective effects and possible mechanism of [Gly14]-humanin (HNG) against Aß-induced deficits in learning behavior. The results showed that bilateral intrahippocampal injection of 2.0 nmol Aß31₋35 significantly increased the mean traveled distance of rats in searching for the hidden underwater platform and decreased the distance percentage in the target quadrant in probe test after withdrawal of platform, whereas pretreatment with HNG (0.2 nmol and 2.0 nmol) suppressed Aß31₋35-induced increase in the traveled distance and decrease in swimming distance percentage. Application of Genistein (40 nmol), a specific tyrosine kinase inhibitor, almost completely blocked the antagonistic effects of HNG against Aß31₋35. These results indicate that HNG can dose-dependently prevent against Aß31₋35-induced impairment in spatial learning and memory of rats, and the neuroprotective effects of HNG might involve the activation of endogenous tyrosine kinase pathway, suggesting that up-regulation of the tyrosine kinase signaling by using HNG might be of great significance for the improvement of cognitive function in AD.

[Recordings of long-term potentiation in rat hippocampal CA1 area with an electrodes-binding technique in vivo].

AIM: To study the feasibility of long-term potentiation(LTP) recording in the CA1 area of the rat in vivo with electrodes-binding technique. METHODS: Anesthetizing Wistar rats with urethane and fixing the animal on the stereotaxic device for acute surgery; implanting cannula into lateral cerebral ventricle; inserting self-made bound stimulating/recording electrodes into hippocampal CA1 area; recording basal field excitatory postsynaptic potential (fEPSP) and tetanus-induced long term potentiation (LTP). RESULTS: fEPSPs were reliably induced by using the stimulating/recording electrodes-binding technique, and the appearance rate of fEPSP was nearly 100%; basal fEPSP recording was very stable, lasting for long time enough to finish all experiment; high frequency stimulation (HFS) successfully induced LTP, which maintained more than three hours, the inductivity is about 67%; paired-pulse facilitation (PPF) recording was also stable; intracerebroventricular (i c v) injection of amyloid beta suppressed HFSinduced LTP evidently. CONCLUSION: The electrodes-binding technique for recording hippocampal LTP in vivo is quite simple and convenient. The experimental resource can be saved, and the rates of fEPSP appearance and LTP induction are kept high. Therefore, it is promising for this technique to be one electrophysiological auxiliary method in the research of learning and memory.

ATP-sensitive potassium channels and endogenous adenosine are involved in spinal antinociception produced by locus coeruleus stimulation.

It has been known that locus coeruleus (LC) stimulation suppresses nociceptive discharges of the thalamic parafascicular (PF) neurons through the spinally descending adrenergic terminals which inhibit the transmission of nociceptive signals in the spinal dorsal horn. This experimental model was used in the present study to analyze the detailed processes that happened in the dorsal horn following norepinephrine release by preemptive intrathecal (i.t.) administration of related drugs in lightly urethane-anesthetized rats. The results showed that: (1) LC stimulation significantly inhibited the noxiously-evoked discharges of PF neurons; (2) the LC stimulation-produced antinociception in PF neurons could be blocked either by i.t. glibenclamide, an ATP-sensitive potassium (K(+)(ATP)) channel blocker, or by i.t. aminophylline, an adenosine receptor antagonist; (3) nociceptive discharges of PF neurons were also suppressed both by i.t. 5 -N-ethylcarboxamido-adenosine (NECA, an adenosine receptor agonist) and by i.t. nicorandil (a K(+)(ATP) channel opener); and (4) i.t. aminophylline blocked the suppression of PF nociceptive discharges induced by i.t. nicorandil, while i.t. glibenclamide showed no effect on the suppression of nociceptive discharges induced by i.t. NECA. These results suggest that: (1) K(+)(ATP) channels and endogenous adenosine may be involved in the mediation of spinal antinociception induced by descending adrenergic fibers originating from the LC; and (2) the opening of K(+)(ATP) channels precedes the release of adenosine in the cascade of mediation.