Impact of the COVID-19 pandemic on antipsychotic prescribing in individuals with autism, dementia, learning disability, serious mental illness or living in a care home: a federated analysis of 59 million patients' primary care records in situ using OpenSAFELY.

BACKGROUND: The COVID-19 pandemic affected how care was delivered to vulnerable patients, such as those with dementia or learning disability. OBJECTIVE: To explore whether this affected antipsychotic prescribing in at-risk populations. METHODS: With the approval of NHS England, we completed a retrospective cohort study, using the OpenSAFELY platform to explore primary care data of 59 million patients. We identified patients in five at-risk groups: autism, dementia, learning disability, serious mental illness and care home residents. We calculated the monthly prevalence of antipsychotic prescribing in these groups, as well as the incidence of new prescriptions in each month. FINDINGS: The average monthly rate of antipsychotic prescribing increased in dementia from 82.75 patients prescribed an antipsychotic per 1000 patients (95% CI 82.30 to 83.19) in January-March 2019 to 90.1 (95% CI 89.68 to 90.60) in October-December 2021 and from 154.61 (95% CI 153.79 to 155.43) to 166.95 (95% CI 166.23 to 167.67) in care homes. There were notable spikes in the rate of new prescriptions issued to patients with dementia and in care homes. In learning disability and autism groups, the rate of prescribing per 1000 decreased from 122.97 (95% CI 122.29 to 123.66) to 119.29 (95% CI 118.68 to 119.91) and from 54.91 (95% CI 54.52 to 55.29) to 51.04 (95% CI 50.74 to 51.35), respectively. CONCLUSION AND IMPLICATIONS: We observed a spike in antipsychotic prescribing in the dementia and care home groups, which correlated with lockdowns and was likely due to prescribing of antipsychotics for palliative care. We observed gradual increases in antipsychotic use in dementia and care home patients and decreases in their use in patients with learning disability or autism.

Cognitive deficits and impaired hippocampal long-term potentiation in KATP-induced DEND syndrome.

ATP-sensitive potassium (KATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited mostly learning and memory deficiencies. Both nKATP-GOF and hKATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP, mildly improved sensorimotor but not cognitive deficits in KATP-GOF mice. Mice expressing KATP-GOF mutations in pancreatic ß-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal KATP-GOF.

Protective Effect of Hydroxysafflor Yellow A against Chronic Mild Stress-induced Memory Impairments by Suppressing Tau Phosphorylation in Mice.

Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease (AD). However, there are currently no effective drugs that can target chronic stress to prevent AD. In this study, we explored the neuroprotective effect of hydroxysafflor yellow A (HSYA) against chronic mild stress (CMS)-induced memory impairments in mice and the underlying mechanism. The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice. HSYA increased the expression of brain-derived neurotrophic factor (BDNF) and activated downstream tropomyosin-related kinase B (TrkB) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/mammalian target of rapamycin (mTOR) signaling. HSYA decreased the expression of regulator of calcineurin 1-1L (RCAN1-1L) that could promote the activity of glycogen synthase kinase-3ß (GSK-3ß). HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3ß and cyclin-dependent kinase-5 (Cdk5). Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation, tau phosphorylation and memory impairments. HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.

Produzindo medicalização: uma revisão bibliográfica sobre encaminhamentos da educação escolar à saúde / Making medicalization: a literature review on school education referrals to health / Produciendo medicalización: revisión bibliográfica sobre derivaciones de la educación escolar a la salud

Este artigo é resultado de uma pesquisa bibliográfica sobre a produção nacional a respeito do encaminhamento de crianças em processo de escolarização a profissionais de saúde, como expressão do processo de medicalização da educação. Realizou-se levantamento bibliográfico na base de dados Biblioteca Virtual em Saúde-Psicologia Brasil/BVS-Psi com os termos: “medicalização”, “medicalização da educação”, “professores e encaminhamentos”, “queixa escolar”, “medicalização na rede pública”, “queixa escolar e medicalização” e “medicalização da queixa escolar”. Selecionaram-se os textos que apresentavam uma perspectiva crítica a respeito dos processos de medicalização da/na educação. Os resultados desta pesquisa indicam que os encaminhamentos são realizados partindo-se de uma concepção de que as dificuldades apresentadas pelas crianças no processo de escolarização são de caráter individual e, dessa forma, passíveis de resolução no campo da saúde. Entretanto, há uma marcante falta de comunicação entre esses serviços e a escola, o que contribui para o recurso ao uso de drogas psicotrópicas como uma das principais medidas para intervir junto às queixas escolares, em detrimento do recurso a novas práticas institucionais da escola.

This article is the result of a bibliographical research on the Brazilian bibliographical production regarding the referral of children in schooling process to health professionals, as an expression of the medicalization process of education. A bibliographical survey was carried out in the database of the Virtual Library of Health/ Psychology Brazil/BVS-Psi under the terms: “medicalization”, “medicalization of education”, “teachers and referrals”, “School complaint and medicalization” and “medicalization of the school complaint”. The researchers selected the texts that presented a critical perspective regarding the medicalization processes of the education. The results indicate that the production of referrals rely on a conception that the difficulties presented by the children in the schooling process, as the school identifies them, are individual in nature and, therefore, can be resolved in the health field. However, there is a lack of communication between these services and the school, which contributes to the use of psychotropic drugs as one of the main measures to intervene with school complaints, rather than making new school practices in order to enhance the schooling process.

Este artículo es el resultado de una investigación bibliográfica sobre la producción brasileña acerca de la derivación de niños en proceso de escolarización a profesionales de salud, como expresión del proceso de medicalización de la educación. Se realizó una revisión de la literatura en la base de datos Biblioteca Virtual en Salud-Psicología Brasil / BVS-Psi con los términos: “medicalización”, “medicalización de la educación”, “profesores y derivaciones”, “queja escolar”, “medicalización en la red pública”, “Queja escolar y medicalización” y “medicalización de la queja escolar “. Se seleccionaron los textos que presentaban una perspectiva crítica acerca de los procesos de medicalización de la educación. Los resultados de esta investigación indican que las derivaciones se realizan partiendo de una concepción de que las dificultades presentadas por los niños en el proceso de escolarización son de carácter individual y de esa forma susceptibles de resolución en el campo de la salud. Sin embargo, hay una marcada falta de comunicación entre estos servicios y la escuela, lo que contribuye al uso de drogas psicotrópicas como una de las principales medidas para intervenir junto a las quejas escolares, en detrimento del recurso a nuevas prácticas institucionales de la escuela.

Pseudoginsenoside-F11 ameliorates okadiac acid-induced learning and memory impairment in rats via modulating protein phosphatase 2A.

We have reported that pseudoginsenoside-F11 (PF11) can significantly improve the cognitive impairments in several Alzheimer's disease (AD) models, but the mechanism has not been fully elucidated. In the present study, the effects of PF11 on AD, in particular the underlying mechanisms related with protein phosphatase 2A (PP2A), were investigated in a rat model induced by okadaic acid (OA), a selective inhibitor of PP2A. The results showed that PF11 treatment dose-dependently improved the learning and memory impairments in OA-induced AD rats. PF11 could significantly inhibit OA-induced tau hyperphosphorylation, suppress the activation of glial cells, alleviate neuroinflammation, thus rescue the neuronal and synaptic damage. Further investigation revealed that PF11 could regulate the protein expression of methyl modifying enzymes (leucine carboxyl methyltransferase-1 and protein phosphatase methylesterase-1) in the brain, thus increase methyl-PP2A protein expression and indirectly increase the activity of PP2A. Molecular docking analysis, structural alignment and in vitro results showed that PF11 was similar in the shape and electrostatic field feature to a known activator of PP2A, and could directly bind and activate PP2A. In conclusion, the present data indicate that PF11 can ameliorate OA-induced learning and memory impairment in rats via modulating PP2A.

Evaluation of the neuroprotective effect of donepezil in type 2 diabetic rats.

Recent studies raise the possibility that donepezil can delay the progression of Alzheimer's disease (AD). This research evaluated the efficacy of donepezil in an animal model with brain insulin resistance and AD-like alterations. Rats were fed with high-fat/high-fructose (HF/Hfr) diet during the study period (17 weeks) and received one injection of streptozotocin (STZ) (25 mg/kg) after 8 weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4 mg/kg; p.o.) or vehicle for 8 weeks after STZ injection. The influence of donepezil on AD-related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid-ß deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P-tau, caspase-3, GSK-3ß, MDA, TNF-α, and IL-1ß in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD-related alterations, including reduction of amyloid-ß burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P-tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D-induced AD and it is still a matter of debate that requires further studies.

Effect of Curcuma zedoaria hydro-alcoholic extract on learning, memory deficits and oxidative damage of brain tissue following seizures induced by pentylenetetrazole in rat.

BACKGROUND: Previous studies have shown that seizures can cause cognitive disorders. On the other hand, the Curcuma zedoaria (CZ) has beneficial effects on the nervous system. However, there is little information on the possible effects of the CZ extract on seizures. The aim of this study was to investigate the possible effects of CZ extract on cognitive impairment and oxidative stress induced by epilepsy in rats. METHODS: Rats were randomly divided into different groups. In all rats (except the sham group), kindling was performed by intraperitoneal injection of pentylenetetrazol (PTZ) at a dose of 35 mg/kg every 48 h for 14 days. Positive group received 2 mg/kg diazepam + PTZ; treatment groups received 100, 200 or 400 mg/kg CZ extract + PTZ; and one group received 0.5 mg/kg flumazenil and CZ extract + PTZ. Shuttle box and Morris Water Maze tests were used to measure memory and learning. On the last day of treatments PTZ injection was at dose of 60 mg/kg, tonic seizure threshold and mortality rate were recorded in each group. After deep anesthesia, blood was drawn from the rats' hearts and the hippocampus of all rats was removed. RESULTS: Statistical analysis of the data showed that the CZ extract significantly increased the tonic seizure threshold and reduced the pentylenetetrazol-induced mortality and the extract dose of 400 mg/kg was selected as the most effective dose compared to the other doses. It was also found that flumazenil (a GABAA receptor antagonist) reduced the tonic seizure threshold compared to the effective dose of the extract. The results of shuttle box and Morris water maze behavioral tests showed that memory and learning decreased in the negative control group and the CZ extract treatment improved memory and learning in rats. The CZ extract also increased antioxidant capacity, decreased MDA and NO in the brain and serum of pre-treated groups in compared to the negative control group. CONCLUSION: It is concluded that the CZ extract has beneficial effects on learning and memory impairment in PTZ-induced epilepsy model, which has been associated with antioxidant effects in the brain or possibly exerts its effects through the GABAergic system.

Flavonoids ameliorate aluminum chloride-induced learning and memory impairments via suppression of apoptosis and oxidative stress in rats.

The study was to investigate the effects of flavonoids (rutin, puerarin, and silymarin) on learning and memory function in rats exposed to aluminum chloride (AlCl3). Wistar rats were administered flavonoids at a dose of 100 mg/(kg·bw)/day or 200 mg/(kg·bw)/day after exposed to 281.40 mg/(kg·bw)/day AlCl3·6H2O. The results of Morris water maze suggested that rutin and puerarin increased the frequency of crossing the platform and swimming time spent in the target quadrant of AlCl3-induced rats significantly. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay indicated that three flavonoids could alleviate apoptosis of hippocampal neurons induced by AlCl3. Real time-PCR and western blot suggested that rutin, puerarin and 100 mg/(kg·bw)/day silymarin could decrease the AlCl3-induced high expression of Bcl-2 associated X protein (Bax) mRNA and protein in hippocampus, but the expression of B cell lymphoma/leukemia-2 (Bcl-2) mRNA and protein was not significantly different among groups. Flavonoids could up regulate the low expression of autophagy related proteins (Beclin 1 (Bcl-2-interacting protein with a coiled-coil domain 1) and LC3 (microtubule-associated protein 1 light chain 3)) caused by AlCl3 exposure. Flavonoids could also adjust the change in adenosine triphosphatase, superoxide dismutase, glutathione peroxidase and malondialdehyde induced by intake of AlCl3. The results of inductively coupled plasma atomic emission spectroscopy (ICP-AES) suggested that flavonoids could effectively reduce the high Al level in brain and serum of AlCl3 exposed rats. In conclusion, three flavonoids may improve learning and memory function by inhibiting excessive apoptosis and oxidative stress in AlCl3 exposed rats.

Neuronal Nitric Oxide Inhibitor 7-Nitroindazole Improved Brain-Derived Neurotrophic Factor and Attenuated Brain Tissues Oxidative Damage and Learning and Memory Impairments of Hypothyroid Juvenile Rats.

Hypothyroidism-associated learning and memory impairment is reported to be connected to oxidative stress and reduced levels of brain-derived neurotrophic factor (BDNF). The effects of neuronal nitric oxide inhibitor 7-nitroindazole (7NI) on brain tissues oxidative damage, nitric oxide (NO), BDNF and memory impairments in hypothyroid juvenile rats were investigated. Male Wistar juvenile rats (20 days old) were divided into five groups, including Martinez et al. (J Neurochem 78 (5):1054-1063, 2001). Control in which vehicle was injected instead of 7NI, (Jackson in Thyroid 8 (10):951-956, 1998) Propylthiouracil (PTU) where 0.05% PTU was added in drinking water and vehicle was injected instead of 7NI, (Gong et al. in BMC Neurosci 11 (1):50, 2010; Alva-Sánchez et al. in Brain Res 1271:27-35, 2009; Anaeigoudari et al. in Pharmacol Rep 68 (2): 243-249, 2016) PTU-7NI 5, PTU-7NI 10 and PTU-7NI 20 in which 5, 10, or 20 mg/kg7NI was injected intraperitoneally (i.p.). Following 6 weeks, Morris water maze (MMW) and passive avoidance learning (PAL) tests were used to evaluate the memory. Finally, the hippocampus and the cortex of the rats were removed after anesthesia by urethane to be used for future analysis. The escape latency and traveled path in MWM test was increased in PTU group (P < 0.001). PTU also reduced the latency to enter the dark box of PAL and the time spent and the distance in the target quadrant in MWM test (P < 0.001 and P < 0.01). Treatment with 7NI attenuated all adverse effects of PTU (P < 0.05 to P < 0.001). PTU lowered BDNF and thiol content and superoxide dismutase (SOD) and catalase (CAT) activities in the brain but increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. In addition, 7NI improved thiol, SOD, CAT, thiol, and BDNF but attenuated MDA and NO metabolites. The results of the current study showed that 7NI improvement in the learning and memory of the hypothyroid juvenile rats, which was accompanied with improving of BDNF and attenuation of NO and brain tissues oxidative damage.

Effect of the King Oyster Culinary-Medicinal Mushroom Pleurotus eryngii (Agaricomycetes) Basidiocarps Powder to Ameliorate Memory and Learning Deficit in Ability in Aß-Induced Alzheimer's Disease C57BL/6J Mice Model.

One of the major causes of Alzheimer's disease (AD) is oxidative stress, which accelerates ß-amyloid peptide (AP) plaque and neurofibrillary tangle accumulation in the brain. Pleurotus eryngii is known to be rich in antioxidants, including ergothioneine, adenosine, and polyphenol, which can reduce oxidative stress-related aging. The aim of this study was to investigate the proximate and functional composition of P. eryngii, and evaluate the cognitive effects of low (LPE), medium (MPE), and high (HPE) P. eryngii dosages in an Aß-induced Alzheimer's disease C57BL/6J mouse model. Mice fed P. eryngii for six weeks showed no adverse effects on body weight gain, food intake efficiency, serum biochemical parameters, and liver and kidney histopathological features. The relative brain weight was significantly lower in Aß-injected mice (p < 0.05). Further, P. eryngii was shown to delay brain atrophy. Reference memory behavioral tasks showed that LPE, MPE, and HPE significantly decreased escape latency (49-85%) and distance (53-69%, p < 0.05). Probe and T-maze tasks showed that P. eryngii potently ameliorated memory deficit in mice. An AD pathology index analysis showed that P. eryngii significantly decreased levels of brain phosphorylated τ-protein, Aß plaque deposition, malondialdehyde, and protein carbonyl (p < 0.05). P. eryngii may therefore promote memory and learning capacity in an Aß-induced AD mouse model.

Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders.

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.

Inhibition of cellular inflammatory mediator production and amelioration of learning deficit in flies by deep sea Aspergillus-derived cyclopenin.

In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1ß, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer's disease, amyloid-ß-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer's model using flies. Learning deficits were induced by the overexpression of amyloid-ß42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.

Ciliary neurotrophic factor signaling in the rat orbitofrontal cortex ameliorates stress-induced deficits in reversal learning.

Deficits in cognitive flexibility, i.e. the ability to modify behavior in response to changes in the environment, are present in several psychiatric disorders and are often refractory to treatment. However, improving treatment response has been hindered by a lack of understanding of the neurobiology of cognitive flexibility. Using a rat model of chronic stress (chronic intermittent cold stress, CIC) that produces selective deficits in reversal learning, a form of cognitive flexibility dependent on orbitofrontal cortex (OFC) function, we have previously shown that JAK2 signaling is required for optimal reversal learning. In this study we explore the molecular basis of those effects. We show that, within the OFC, CIC stress reduces the levels of phosphorylated JAK2 and of ciliary neurotrophic factor (CNTF), a promoter of neuronal survival and an activator of JAK2 signaling, and that neutralizing endogenous CNTF with an intra-OFC microinjection of a specific antibody is sufficient to produce reversal-learning deficits similar to stress. Intra-OFC delivery of recombinant CNTF to CIC-stressed rats, at a dose that induces JAK2 and Akt but not STAT3 or ERK, ameliorates reversal-learning deficits, and Akt blockade prevents the positive effects of CNTF. Further analysis revealed that CNTF may exert its beneficial effects by inhibiting GSK3ß, a substrate of Akt and a regulator of protein degradation. We also revealed a novel mechanism of CNTF action through modulation of p38/Mnk1/eIF4E signaling. This cascade controls translation of select mRNAs, including those encoding several plasticity-related proteins. Thus, we suggest that CNTF-driven JAK2 signaling corrects stress-induced reversal learning deficits by modulating the steady-state levels of plasticity-related proteins in the OFC.

Role of JNK Signaling Pathway in Dexmedetomidine Post-Conditioning-Induced Reduction of the Inflammatory Response and Autophagy Effect of Focal Cerebral Ischemia Reperfusion Injury in Rats.

To investigate the effect of dexmedetomidine post-conditioning on the inflammatory response and autophagy effect of focal cerebral ischemia reperfusion injury in rats, and further to study its potential mechanisms. Water maze was conducted to evaluate spatial learning and memory ability of middle cerebral artery occlusion (MCAO) rats. TTC staining was used to observe the area of cerebral infarction. The expressions of inflammatory factors in serum were detected by ELISA. TUNEL assay, HE staining, and transmission electron microscopy were used to detect the apoptosis of neurons, neuro-cytopathic changes, and the formation of auto-phagosome in hippocampus CA1 region, respectively. The mRNA and protein expression of Beclin-1, Caspase-3, and light chain 3 (LC3) were detected by qRT-PCR and Western blot. Moreover, the activity of C-Jun N-terminal kinase (JNK) pathway was detected by Western blot. The escape latency (EL); cerebral infarction area ratio; positive apoptosis; neuron pathological changes; auto-phagosome numbers; inflammatory factor contents; mRNA and protein expressions of Beclin-1, Caspase-3 and LC3II/I; and the phosphorylation level of JNK were decreased, while the times across platform and the times stayed in the quadrant of the original platform were increased after dexmedetomidine treatment. However, the protective effect of dexmedetomidine on brain injury in MCAO rats was reversed by JNK pathway activator. Dexmedetomidine post-conditioning could improve learning and memory dysfunction caused by MCAO in rats and reduce the inflammatory response and autophagy effect. The mechanism may be related to inhibition of JNK pathway activation.

Allicin alleviated learning and memory deficits caused by lead exposure at developmental stage.

AIMS: It is a promising approach to search the therapeutic strategies for treating lead (Pb) toxicity. Allicin, a natural compound extracted from Allium sativum (garlic), has been reported to have many beneficially biological properties. In this study, we investigated the protective effects of allicin on learning and memory function of rats exposed by lead acetate at developmental stage. MATERIALS AND METHODS: Rats received lead acetate for inducing toxicity, and gavaged with allicin to ameliorate this toxicity. Morris water maze test was performed to determine learning and memory function. Superoxide dismutase (SOD), glutathione (GSH) and methane dicarboxylic aldehyde (MDA) was measured to determine oxidative stress. Immunofluorescence was carried out to analyze GFAP-positive cells. The protein expression of ERK, p-ERK, EGFR and p-EGFR were detected using western blot. KEY FINDINGS: We found that allicin ameliorated lead acetate-caused learning and memory deficits by promoting hippocampus astrocyte differentiation, which mainly through EGFR/ERK signaling. Moreover, allicin attenuated the increased ROS level by regulating the oxidative defense system. SIGNIFICANCE: These results suggest that allicin is a potent agent able to ameliorate lead acetate-induced learning and memory deficits during early development, and may thus be useful for defeating lead acetate toxicity.

Antidepressant and Neuroprotective Effects of Naringenin via Sonic Hedgehog-GLI1 Cell Signaling Pathway in a Rat Model of Chronic Unpredictable Mild Stress.

Depression is one of the most prevalent and crucial public health problem connected to significant mortality and co-morbidity. Recently, numerous studies suggested that dietary flavanones exhibit neuroprotective and antidepressant effects against various psycho-physiological conditions including depression. The present study is focused on the antidepressant and neuroprotective effects of naringenin (NAR) and the involvement of sonic hedgehog (Shh) signaling in the chronic unpredictable mild stress (CUMS)-induced depression. Twenty-four male Wistar rats were randomly assigned into four groups: CON group (saline s.c.), NAR group (NAR 50 mg/kg, p.o.), CUMS group (subjected to CUMS along with saline p.o.), and CUMS + NAR group (NAR 50 mg/kg p.o. along with CUMS) for 28 days including 1-week pre-treatment with NAR. The results showed that NAR was found to inhibit behavioral abnormalities including increased despair in force swim test, and reduced locomotor activity caused by CUMS in open field test. Moreover, Morris water maze revealed that NAR also mitigates CUMS-associated cognitive impairment. In addition to the antidepressant-like effect, NAR mitigates morphological anomalies in the hippocampal CA1 region and cortex. Furthermore, we observed brain-derived neurotrophic factor (BDNF), Shh, GLI1, NKX2.2, and PAX6 were downregulated in the hippocampus of CUMS-exposed rats, which can be upregulated by NAR pre-treatment. GLI1 is main downstream signaling component of Shh signaling cascade, which further regulates the expression of homeodomain transcription factors PAX6 and NKX2.2.

Quercetin promotes learning and memory performance concomitantly with neural stem/progenitor cell proliferation and neurogenesis in the adult rat dentate gyrus.

The decline in neurogenesis is a very critical problem in Alzheimer disease. Different biological activities have been reported for medicinal application of quercetin. Herein, we investigated the neurogenesis potential of quercetin in a rat model of Alzheimer's disease induced by amyloid-beta injection. Rats were randomly divided into Control, Alzheimer + Saline and Alzheimer + Quercetin groups. Following the administration of Amyloid-beta, rats in the Alzheimer + Quercetin group received 40 mg/kg/day quercetin orally for one month. Our data demonstrated amyloid-ß injection could impair learning and memory processing in rats indicated by passive avoidance test evaluation. We noted that one-month quercetin treatment alleviated the detrimental effects of amyloid-ß on spatial learning and memory parameters using Morris water maze analysis. Quercetin was found to increase the number of proliferating neural stem/progenitor cells. Notably, quercetin increased the number of DCX-expressing cells, indicating the active dynamic growth of neural progenitor cells in the dentate gyrus of the hippocampus. We further observed that the quercetin improved the number of BrdU/NeuN positive cells contributed to enhanced adult neurogenesis. Based on our results, quercetin had the potential to promote the expression of BDNF, NGF, CREB, and EGR-1 genes involved in regulating neurogenesis. These data suggest that quercetin can play a valuable role in alleviating Alzheimer's disease symptoms by enhancing adult neurogenesis mechanism.

Fluoxetine reverses brain radiation and temozolomide-induced anxiety and spatial learning and memory defect in mice.

Radiation therapy and concomitant temozolomide chemotherapy are commonly used in treatment of brain tumors, but they may also result in behavioral impairments such as anxiety and cognitive deficit. The present study sought to investigate the effect of fluoxetine on the behavioral impairments caused by radiation and temozolomide treatment. C57BL/6J mice were subjected to a single cranial radiation followed by 6-wk cyclic temozolomide administration and were then treated with chronic administration of fluoxetine. Behavioral tests were carried out to determine the anxiety-like behavior and cognition function of these animals. Long-term potentiation (LTP) in the hippocampus was measured by electrophysiology, and neurogenesis in the dentate gyrus was evaluated by immunohistochemistry. Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment, along with LTP impairment and neurogenesis deficit. Chronic fluoxetine administration could reverse the behavioral dysfunction, enhance LTP, and increase neurogenesis in the hippocampus. NEW & NOTEWORTHY Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment. Chronic fluoxetine administration could reverse the behavioral dysfunction. The effect of fluoxetine might be via rescuing the neurogenesis deficit caused by radiation and temozolomide treatment.

Effects of porcine brain hydrolysate on impairment of cognitive learning ability in amyloid ß(1-40) -infused rats.

This study assessed whether administering porcine brain hydrolysate (PBH) ameliorates the impairment of spatial cognition learning ability in amyloid ß (Aß)-infused rats. PBH was prepared using organic solvents (i.e., acetone and ethanol). Enzyme hydrolysates were derived from these PBH and the sequence of the Aß peptide for infusion was selected. The results indicated the PBH, in particular EP (porcine brain extract with ethanol and protease N), demonstrated the potentials to reduce damage of neurodegenerative disorders in vitro and in vivo. The principal findings of this study indicate that PBH has prolyl endopeptidase inhibitory activity in vitro. Moreover, administering EP to Aß(1-40)-infused rats significantly improves their performance on reference, spatial performance, and working memory tests during water maze tasks; concurrent proportional decreases are also observed in malondialdehyde levels, acetylcholinesterase (AChE) activity, and Aß accumulation levels in brain tissues. The PBH was suggested to ameliorate learning deficits associated with Alzheimer's disease by inhibition of lipid peroxidation in the brain of Aß infused rat.

Surgical incision induces learning impairment in mice partially through inhibition of the brain-derived neurotrophic factor signaling pathway in the hippocampus and amygdala.

Surgical incision-induced nociception contributes to the occurrence of postoperative cognitive dysfunction. However, the exact mechanisms involved remain unclear. Brain-derived neurotrophic factor (BDNF) has been demonstrated to improve fear learning ability. In addition, BDNF expression is influenced by the peripheral nociceptive stimulation. Therefore, we hypothesized that surgical incision-induced nociception may cause learning impairment by inhibiting the BDNF/tropomyosin-related kinase B (TrkB) signaling pathway. The fear conditioning test, enzyme-linked immunosorbent assay, and Western blot analyses were used to confirm our hypothesis and determine the effect of a plantar incision on the fear learning and the BDNF/TrkB signaling pathway in the hippocampus and amygdala. The freezing times in the context test and the tone test were decreased after the plantar incision. A eutectic mixture of local anesthetics attenuated plantar incision-induced postoperative pain and fear learning impairment. ANA-12, a selective TrkB antagonist, abolished the improvement in fear learning and the activation of the BDNF signaling pathway induced by eutectic mixture of local anesthetics. Based on these results, surgical incision-induced postoperative pain, which was attenuated by postoperative analgesia, caused learning impairment in mice partially by inhibiting the BDNF signaling pathway. These findings provide insights into the mechanism underlying surgical incision-induced postoperative cognitive function impairment.