Treatment Of Memory Impairment Research Articles

Chronic molecular hydrogen inhalation mitigates short and long-term memory loss in polymicrobial sepsis

The central nervous system (CNS) is one of the first physiological systems to be affected in sepsis. During the exacerbated systemic inflammatory response at the early stage of sepsis, circulatory inflammatory mediators are able to reach the CNS leading to neuroinflammation and, consequently, long-term impairment in learning and memory formation is observed. The acute treatment with molecular hydrogen (H2) exerts important antioxidative, antiapoptotic, and anti-inflammatory effects in sepsis, but little is known about the mechanism itself and the efficacy of chronic H2 inhalation in sepsis treatment. Thus, we tested two hypotheses. We first hypothesized that chronic H2 inhalation is also an effective therapy to treat memory impairment induced by sepsis. The second hypothesis is that H2 treatment decreases sepsis-induced neuroinflammation in the hippocampus and prefrontal cortex, important areas related to short and long-term memory processing. Our results indicate that (1) chronic exposure of hydrogen gas is a simple, safe and promising therapeutic strategy to prevent memory loss in patients with sepsis and (2) acute H2 inhalation decreases neuroinflammation in memory-related areas and increases total nuclear factor E2-related factor 2 (Nrf2), a transcription factorthat regulates a vast group of antioxidant and inflammatory agents expression in these areas of septic animals.

Genetic and metabolic links between the murine microbiome and memory

BackgroundRecent evidence has linked the gut microbiome to host behavior via the gut–brain axis [1–3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice.ResultsA genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice.ConclusionTogether, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites.8Wgvn7aSo1UtQ-gTeXXmu8Video

Galanthamine and other Amaryllidaceae related alkaloids are inhibitors of α7, α4β2 and α3β4 nicotinic acetylcholine receptors

Galanthamine is an Amaryllidaceae-derived acetylcholinesterase inhibitor used to treat memory impairment in Alzheimer's disease and vascular dementia. There is evidence that galanthamine, in addition to its effects on acetylcholinesterase, may enhance or inhibit brain nicotinic acetylcholine receptors, which could increase or decrease the therapeutic efficacy of galanthamine, respectively. Here, we evaluated the effects of galanthamine and two others Amaryllidaceae acetylcholinesterase inhibitors (haemanthamine and tazettine) analyzed by gas chromatography–mass spectrometry and identified by comparing their mass fragmentation patterns with literature and database NIST vs.2.0 on the agonist responses of brain nicotinic acetylcholine receptors α7, α3β4, (α4)2(β2)3 and (α4)3(β2)2. Using nicotinic acetylcholine receptors expressed heterologously in Xenopus oocytes, in conjunction with two-electrode voltage clamping, we found that galanthamine inhibits the function of nicotinic acetylcholine receptors assayed through a mix competitive and non-competitevely. Nicotinic acetylcholine receptor α7 were significantly more sensitive to inhibition (17±0.6μM) than the heteromeric receptor, α3β4 (90±3.4μM). Neither haemanthamine nor tazettine were more potent than galanthamine.

Optogenetic Stimulation of the M2 Cortex Reverts Motor Dysfunction in a Mouse Model of Parkinson's Disease

Neuromodulation of deep brain structures (deep brain stimulation) is the current surgical procedure for treatment of Parkinson's disease (PD). Less studied is the stimulation of cortical motor areas to treat PD symptoms, although also known to alleviate motor disturbances in PD. We were able to show that optogenetic activation of secondary (M2) motor cortex improves motor functions in dopamine-depleted male mice. The stimulated M2 cortex harbors glutamatergic pyramidal neurons that project to subcortical structures, critically involved in motor control, and makes synaptic contacts with dopaminergic neurons. Strikingly, optogenetic activation of M2 neurons or axons into the dorsomedial striatum increases striatal levels of dopamine and evokes locomotor activity. We found that dopamine neurotransmission sensitizes the locomotor behavior elicited by activation of M2 neurons. Furthermore, combination of intranigral infusion of glutamatergic antagonists and circuit specific optogenetic stimulation revealed that behavioral response depended on the activity of M2 neurons projecting to SNc. Interestingly, repeated M2 stimulation combined with l-DOPA treatment produced an unanticipated improvement in working memory performance, which was absent in control mice under l-DOPA treatment only. Therefore, the M2-basal ganglia circuit is critical for the assembly of the motor and cognitive function, and this study demonstrates a therapeutic mechanism for cortical stimulation in PD that involves recruitment of long-range glutamatergic projection neurons.SIGNIFICANCE STATEMENT Some patients with Parkinson's disease are offered treatment through surgery, which consists of delivering electrical current to regions deep within the brain. This study shows that stimulation of an area located on the brain surface, known as the secondary motor cortex, can also reverse movement disorders in mice. Authors have used a brain stimulation technique called optogenetics, which allowed targeting a specific type of surface neuron that communicates with the deep part of the brain involved in movement control. The study also shows that a combination of this stimulation with drug treatment might be useful to treat memory impairment, a kind of cognitive problem in Parkinson's disease.

Rhodiola rosea root extract has antipsychotic-like effects in rodent models of sensorimotor gating

Ethnopharmacological relevanceThe plant arctic root (Rhodiola rosea, L.) is growing in northern regions of Europe, Asia and North America. Extracts of R. rosea are used in traditional medicine for various conditions related to nervous system function. According to scientific studies from the last decades, the plant might have potential for use in the treatment of memory impairments, stress and depression, but reports concerning other neuropsychiatric disorders are scarce. Aim of the studyIn this context, our study aimed to examine potential antipsychotic-like effects of R. rosea root extract. Materials and methodsWe tested the effects of R. rosea root extract on prepulse inhibition in rats and mice. Prepulse inhibition is an established operational measure of sensorimotor gating, which is impaired in schizophrenia and other psychotic disorders. ResultsR. rosea root extract increased prepulse inhibition in rats and mice. Interestingly, the R. rosea extract had stronger effects in those individual animals that had low baseline levels of prepulse inhibition. Therefore, we performed further experiments in which we pharmacologically induced a prepulse inhibition deficit by two different psychostimulants, either the dopamine D2 receptor agonist apomorphine or the NMDA receptor antagonist dizocilpine (MK-801). Pre-treatment with the R. rosea extract significantly restored both, apomorphine- and dizocilpine-induced prepulse inhibition deficits. ConclusionsThe present study demonstrates that R. rosea extract robustly reverses prepulse inhibition deficits in rodents. This suggests antipsychotic-like effects of R. rosea extract. Future studies should focus on the pharmacological mechanisms underlying these effects.

Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus.

Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.

Comparative toxicity and toxicokinetic studies of oxiracetam and (S)-oxiracetam in dogs

Oxiracetam (ORT) is known as a derivative of piracetam in the family of nootropics for treating memory impairment and cognition disorders.Given the chiral toxicological concerns surrounding ORT and the absence studies of (S)-ORT, the toxicity and toxicokinetics of (S)-ORT, and comparative toxicology of oxiracetam were systematically investigated in dogs following acute and 13-week repeated oral dosing.The animal toxicity mainly manifested as loose stools in both the acute and the 13-week studies. The no-observed-adverse-effect level is proposed to be 100 mg/kg. The 13-week toxicokinetics study indicated that, in the (S)-ORT group, the time to peak concentration was delayed, elimination half-life extended, and apparent volume of distribution increased compared with the ORT group. The clearance rate increased at low- and mid-doses, but decreased in the high-dose group and was accompanied by drug accumulation. Compared with the same dose of ORT, (S)-ORT had a lower clearance rate and longer elimination half-life.

The effects and mechanisms of the action of galangin on spatial memory in rats.

Galangin, a flavonoid compound with acetylcholinesterase inhibitory activity, may improve cognitive functions by enhancing cholinergic transmission. We aimed to investigate the effects of galangin on spatial memory impairment in rats. The effects of galangin (50 and 100 mg/kg) and reference anti-dementia drug donepezil (1mg/kg) administrations were examined on memory impairment induced by the muscarinic cholinergic receptor antagonist scopolamine or the nicotinic cholinergic receptor antagonist mecamylamine in the Morris water maze (MWM) test. Hippocampal acetylcholine concentrations were also determined. Galangin 50 and 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in scopolamine-treated rats. Galangin 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in mecamylamine-treated rats. The effects of galangin in the MWM were comparable with donepezil. Scopolamine and mecamylamine decreased acetylcholine concentrations, whereas galangin both alone and with mecamylamine or scopolamine administration increased acetylcholine concentrations. Galangin improved memory impairment comparable to donepezil and nicotinic and muscarinic receptors may be involved in this effect. Galangin may be considered as a promising flavonoid in the prevention and treatment of memory impairment in Alzheimer's disease and other dementias (Fig. 7,Ref. 37).

Phytochemical screening and evaluation of neuroprotective, anti-mutagenic and anti-genotoxic effects of Turkish endemic Glaucium acutidentatum

Glaucium species (Papaveraceae) are the medicinal plant that has been used traditionally to have been used for centuries to treat memory impairment. The aim of this study is to investigate the G. acutidentatum methanol and water extracts' phytochemicals and neuroprotective, anti-inflammatory, anti-mutagenic and anti-genotoxic potentials.Chemical composition was screened by using capillary gas chromatography–mass spectrometry (GC–MS). Neuroprotective effect was analyzed on nerve growth factor (NGF) differentiated-PC12 (dPC12) cells from neuroinflammation and neurodegeneration. Also, these extracts were screened for the mutagenic and anti-mutagenic activity by the Salmonella/microsome test system. In addition, genotoxic profiles and anti-genotoxic effects of these extracts were also analyzed by Comet technique.Extracts of G. acutidentatum had strong neuroprotective effects against hydrogen peroxide (H2O2)-induced damage. Also, neurite length was dose-dependently increased in extracts exposed groups compared with the H2O2-treated group. The anti-inflammatory effect of these extracts was parallel to neuroprotective effect. However, these extracts showed strong anti-mutagenicity (72.9–75.0%) and anti-genotoxic properties. Any genotoxic effect was observed of these extracts in lymphocyte cells, analyzed by the Comet assay.These results suggest that methanol and water extracts of G. acutidentatum had neuroprotective and anti-mutagenic effects and contained protective substances that decreasing damage to genetic material.

Protective effect of water extract of guibi-tang against pulmonary inflammation induced by cigarette smoke and lipopolysaccharide

Water extract of guibi-tang (GB), a traditional Chinese, Japanese, and Korean herbal medicine, is used to treat memory impairment, insomnia, and peptic ulcers. The aim of this study was to investigate the protective effects of GB on pulmonary inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS). C57BL/6 mice were used to develop a pulmonary inflammation model by exposing them to CS for 1 h per day for 7 days. LPS was intranasally administered to mice under mild anesthesia on day 5. GB was administered 1 h before CS exposure at doses of 50 or 100 mg/kg for 7 days. Our results showed that GB suppressed the CS and LPS induced elevation in inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), with significant reductions in protein, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels. Histological studies revealed that GB decreased the inflammatory cell infiltration into lung tissue caused by CS- and LPS-exposure. GB also significantly decreased the CS and LPS-induced expression of inducible nitric oxide synthase (iNOS) in the lung tissue. Taken together, GB effectively attenuated airway inflammation caused by CS and LPS. These results indicate that GB is a potential therapeutic herbal formula for pulmonary inflammatory disease.

Treadmill exercise attenuates 3,4-methylenedioxymethamphetamine-induced memory impairment through a decrease apoptosis in male rat hippocampus.

3,4-methylenedioxymethamphetamine (MDMA) leads to apoptosis in the hippocampus with consequent induction of learning and memory impairment. In this study, we have investigated the effects of treadmill exercise on memory in relation to apoptosis and oxidative stress in the hippocampi of MDMA-treated rats. Male Wistar rats received multiple intraperitoneal (IP) injections of MDMA (10 mg/kg) and exercised for one month on a treadmill (simultaneously or asynchronously with MDMA). We assessed memory function with the Morris water maze (MWM) test. Lipid peroxidation (LPO) and expression of caspase 3, Bax, and Bcl-2 were examined by the thiobarbituric acid assay (TBA) and western blot, respectively. Our results showed that asynchronous treadmill exercise could significantly improve MDMA-induced memory impairment in the MWM test. Caspase 3 expression decreased in the exercise group compared to the MDMA group. Although MDMA treatment caused an increase in the Bax/Bcl-2 ratio, the treadmill exercise reduced this ratio. Simultaneous exercise caused a reduction in lipid peroxidation in the hippocampus. This data suggests that treadmill exercise can be a useful strategy for treating memory impairment in persons with neurodegenerative disease and stimulant drug users. © 2017 Wiley Periodicals, Inc.

Rhodiola rosea L extract shows protective activity against Alzheimer’s disease in 3xTg-AD mice

Purpose: To investigate the protective effect of Rhodiola rosea L. extract (RRLE) against Alzheimer's disease in 3xTg-AD mice.Methods: The cognitive function of 3xTg-AD mice was assessed using Morris water maze test. The levels of amyloid beta deposits and NeuN in the hippocampus were evaluated by immunohistochemistry. Brain neurotrophic-derived factor (BDNF) and tyrosine kinase B (TrkB) expressions were examined by western blot analysis.Results: RRLE treatment significantly ameliorated learning and memory deficits in AD mice, as shown by increased time spent in the target zone during probe tests. The escape latency in animals treated with 400 mg/kg RRLE (20.5 ± 1.3 s) was significantly increased compared to the untreated mice (12.4 ± 1.3 s, p < 0.01). In addition, RRLE significantly decreased Aβ deposits, increased NeuN-positive cells, and upregulated the expression of BDNF (1.4 ± 0.2, p < 0.05) and TrkB (1.1 ± 0.2, p < 0.05) in the mice.Conclusion: The findings suggest that RRLE treatment may be a useful strategy for treating memory impairment induced by several neurodegenerative diseases.Keywords: Rhodiola rosea L., Alzheimer's disease, Neurodegenerative diseases, Memory impairment, NeuN-positive cells, Amyloid beta deposits

A Smart Block for Haptic Interface with Virtual Reality Contents for Mild Cognitive Impairment Patients

The goal of this paper is to implement a haptic interface device for virtual reality application for the patients with MCI(Mild Cognitive Impairment) to recover their lost memory. The physical therapy for treatment of MCI is being developed as a complementary method for the treatment of memory impairment in the elderly. To produce a VR treatment program for memory recovery, the interactive program running on a virtual environment needs to be designed to be reminiscent of the memories in the past with a smart block haptic device that uses the force feedback mechanism from the user’s hands. To this end, we propose the smart block scheme implemented with an embedded system based on the virtual reality application to support treating and recovering memory for the elderly patients.

IMPAIRED OBJECT RECOGNITION MEMORY AND ACETYLCHOLINESTERASE ACTIVITY IN ANIMAL MODEL OF POST-TRAUMATIC STRESS DISORDER-RESTORED BY ECLIPTA ALBA LINN. A DIETARY HERB.

ABSTRACTObjective: Acetylcholinesterase (AChE) inhibitors are important therapeutic targets to treat memory impairment caused due to stress, post-traumaticstress disorder (PTSD) results from traumatic stress exposure. Cognition and mood symptoms can begin or worsen after the traumatic event. In thisstudy, we aimed to evaluate the role of Eclipta alba Linn. as an antistressor, AChE inhibitor, and on object recognition memory in an animal model of PTSD.Methods: Adult male Wistar albino rats were randomly divided into four groups: Control, chronic unpredictable stress (CUS) (30 days), CUS+ethanolicextract of E. alba (EEEA) (200 mg/kg body weight), and EEEA (200 mg/kg body weight) treatment groups and were assessed for novel objectrecognition task (NORT), plasma corticosterone, and AChE activity.Results: We found significant improvement in NORT (p<0.05) plasma corticosterone levels in stress group was significantly increased (p<00.05)which is resumed with EEEA treatment (p<0.05) AChE activity was found to be reduced after EEEA treatment.Conclusion: EEEA is found to possess cognitive enhancing activity in the animal model of PTSD.Keywords: Recognition memory,PTSD,Unpredictable stress,Eclipta alba

Aide memoire: What should a memory clinic or a memory assessment service look like?

With the global ageing of our societies and the predicted increase of cognitive impairment and dementia, there is increasing interest in the role and scope of memory clinics or memory assessment services in the early assessment, diagnosis and management of all subtypes of dementia. Memory clinics generally attempt to provide a multidisciplinary approach to the diagnosis and treatment of memory impairment and dementia. However, little consensus exists about the profile or complement of staff that would constitute an ideal memory clinic, and services vary widely in terms of their organisation, remit and functioning. The purpose of this article is to highlight the variation amongst the existing complement of memory clinics in Ireland. The 17 models are compared in terms of their core multidisciplinary service and services available on referral. The Irish National Dementia Strategy recommends a well-coordinated service that provides early diagnosis and treatment, and one with good links to local support agencies. However, many of the services in Ireland lack input from relevant allied health professionals. This article also focusses on one privately funded memory clinic in Ireland which aims to bridge the gap between accurate diagnosis, holistic assessment and follow-up through comprehensive multidisciplinary input. The challenges facing this service are discussed, with particular reference to the difficulties encountered when providing community follow-up by a private sector clinic.

Nerolidol-loaded nanospheres prevent behavioral impairment via ameliorating Na+, K+-ATPase and AChE activities as well as reducing oxidative stress in the brain of Trypanosoma evansi-infected mice.

The aim of this study was to investigate the effect of nerolidol-loaded nanospheres (N-NS) on the treatment of memory impairment caused by Trypanosoma evansi in mice, as well as oxidative stress, and Na+, K+-ATPase and acetylcholinesterase (AChE) activities in brain tissue. Animals were submitted to behavioral tasks (inhibitory avoidance task and open-field test) 4days postinfection (PI). Reactive oxygen species (ROS) and thiobarbituric acid-reactive substance (TBARS) levels and catalase (CAT), superoxide dismutase (SOD), Na+, K+-ATPase and AChE activities were measured on the fifth-day PI. T. evansi-infected mice showed memory deficit, increased ROS and TBARS levels and SOD and AChE activities, and decreased CAT and Na+, K+-ATPase activities compared to uninfected mice. N-NS prevented memory impairment and oxidative stress parameters (except SOD activity), while free nerolidol (N-F) restored only CAT activity. Also, N-NS treatment was able to prevent alterations in Na+, K+-ATPase and AChE activities caused by T. evansi infection. A significantly negative correlation was observed between memory and ROS production (p<0.001; r=-0.941), as well as between memory and AChE activity (p<0.05; r=-0.774). On the contrary, a significantly positive correlation between memory and Na+, K+-ATPase activity was observed (p<0.01; r=0.844). In conclusion, N-NS was able to reverse memory impairment and to prevent increased ROS and TBARS levels due to amelioration of Na+, K+-ATPase and AChE activities and to activation of the antioxidant enzymes, respectively. These results suggest that N-NS treatment may be a useful strategy to treat memory dysfunction and oxidative stress caused by T. evansi infection.

Minocycline ameliorates d-galactose-induced memory deficits and loss of Arc/Arg3.1 expression

Dysfunction of learning and memory is widely found in many neurological diseases. Understanding how to preserve the normal function of learning and memory will be extremely beneficial for the treatment of these diseases. However, the possible protective effect of minocycline in memory impairment is unknown. We used the well-established D-galactose rat amnesia model and two behavioral tasks, the Morris water maze and the step-down task, for memory evaluation. Western blot and PCR were used to examine the protein and mRNA levels of Arc/Arg3.1. We report that minocycline supplementation ameliorates both the spatial and fear memory deficits caused by D-galactose. We also found that Arc/Arg3.1, c-fos, and brain-derived neurotrophic factor levels are decreased in the D-galactose animal model, and that minocycline reverses the protein and mRNA levels of Arc in the hippocampus, suggesting the potential role of Arc/Arg3.1 in minocycline's neuroprotective mechanism. Our study strongly suggests that minocycline can be used as a novel treatment for memory impairment in neurological diseases.

IMPROVING COGNITIVE FUNCTION IN RODENTS VIA INCREASING GLYCINE LEVELS IN BRAIN BY THE NOVEL GLYCINE TRANSPORTER-1 INHIBITOR BI 425809

Dysfunction of the glutamatergic system related to the NMDA receptor may play an important role in cognitive impairment in Alzheimer’s disease. One approach to counteract this is the extracellular increase of the NMDA receptor co-agonist glycine by glycine transporter-1 (GlyT1) inhibition. Thus, inhibiting GlyT1 has potential for treating memory impairment in Alzheimer’s disease via strengthening glutamatergic neurotransmission. Previous studies with GlyT1-inhibitors show memory-enhancing effects in animals. This study characterizes the potency and selectivity of the novel GlyT1 inhibitor BI 425809 and its effects on glycine increase in rat cerebrospinal fluid (CSF). BI 425809 was also evaluated in two rodent cognition tasks assessing episodic memory and working memory. The molecular potency of BI 425809 for GlyT1 was determined by inhibition of [3H]-glycine uptake in human SK-N-MC cells and rat primary cortical neurons. Selectivity was tested against GlyT2 and other off-targets by uptake and receptor binding assays, respectively. Concentrations of glycine in rat CSF samples collected from cisterna magna following oral administration of BI 425809 were determined by HPLC-MS/MS technique. BI 425809 was tested after oral application in the mouse T-maze spontaneous alternation test and in the social recognition test in naive rats. The IC50 value of BI 425809 on GlyT1 was 4.0 nM in SK-N-MC cells and 4.4 nM in rat primary neurons. BI 425809 demonstrated no relevant activity against GlyT2 (IC50 >10 μM) and 103 off-targets at 10 μM. A dose-dependent increase of glycine in rat CSF was observed. BI 425809 reversed MK-801-induced memory deficits in the mouse T-maze (working memory) and improved memory performance in the rat social recognition task (episodic memory). BI 425809 is a potent and selective GlyT1 inhibitor. Systemic administration of BI 425809 led to an increase in glycine levels in rat CSF demonstrating functional target engagement – i.e. GlyT1 inhibition in the brain – showing that glycine levels in CSF can be used to assess GlyT1 inhibition centrally. This might also be used to evaluate central target engagement in clinical trials. BI 425809 showed memory enhancing effects in animal cognition tests. GlyT1 inhibition may be a potential approach to pharmacologically improve cognition in Alzheimer’s disease.

Interictal epileptiform discharges induce hippocampal-cortical coupling in temporal lobe epilepsy.

Interactions between the hippocampus and cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but how they interact with physiological patterns of network activity is mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation and are precisely coordinated with spindle oscillations in the prefrontal cortex during NREM sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during REM sleep and wakefulness, behavioral states that do not naturally express these oscillations, by generating a cortical ‘DOWN’ state. We confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions in a pilot clinical examination of four subjects with focal epilepsy. These findings imply that IEDs may impair memory via misappropriation of physiological mechanisms for hippocampal-cortical coupling, suggesting a target to treat memory impairment in epilepsy.

The anti-dementia drug candidate, (−)-clausenamide, improves memory impairment through its multi-target effect

Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca(2+) concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca(2+) overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.