Diverse learners: learning disabilities and quality of life following mind-body and health education interventions for adults with neurofibromatosis.

PURPOSE: Neurofibromatosis (NF) is associated with low quality-of-life (QoL). Learning disabilities are prevalent among those with NF, further worsening QoL and potentially impacting benefits from mind-body and educational interventions, yet research on this population is scarce. Here, we address this gap by comparing NF patients with and without learning disabilities on QoL at baseline and QoL-related gains following two interventions. METHODS: Secondary analysis of a fully-powered RCT of a mind-body program (Relaxation Response Resiliency Program for NF; 3RP-NF) versus an educational program (Health Enhancement Program for NF; HEP-NF) among 228 adults with NF. Participants reported QoL in four domains (Physical Health, Psychological, Social Relationships, and Environmental). We compare data at baseline, post-treatment, and 12-month follow-up, controlling for intervention type. RESULTS: At baseline, individuals with NF and learning disabilities had lower Psychological (T = -3.0, p = .001) and Environmental (T = -3.8, p < .001) QoL compared to those without learning disabilities. Both programs significantly improved all QoL domains (ps < .0001-0.002) from baseline to post-treatment, regardless of learning disability status. However, those with learning disabilities exceeded the minimal clinically important difference in only one domain (Psychological QoL) compared to three domains in individuals without learning disabilities. Moreover, those with learning disabilities failed to sustain statistically significant gains in Psychological QoL at 12-months, while those without learning disabilities sustained all gains. CONCLUSION: Adults with NF and learning disabilities have lower Psychological and Environmental QoL. While interventions show promise in improving QoL regardless of learning disabilities, additional measures may bolster clinical benefit and sustainability among those with learning disabilities.

Autobiographical memory and future thinking impairments in multiple sclerosis: Cognitive and neural mechanisms, functional impact and rehabilitation.

Learning and memory impairments are common in individuals with multiple sclerosis (MS) and have pervasive effects on everyday life functioning. Hence, memory and learning have received particular attention in the cognitive rehabilitation literature in MS. The effectiveness of memory rehabilitation on memory performance is supported by several studies, but the generalisability of the benefits to daily life and memory for real-life events has rarely been examined. Recently, a new line of research focusing on memory for personal life events (i.e., autobiographical memory) has emerged in the MS literature. This approach is complementary to classical learning and memory paradigms and also allows for approaching memory in a broader context, one that considers memory as the ability to remember past episodes and imagine events that may occur in one's personal future (i.e. future thinking). This review provides an overview of the findings in this line of work. The first part summarises current evidence regarding the cognitive and neural mechanisms underlying autobiographical memory and future thinking impairments in MS. It points out that these domains are frequently and early impaired in individuals with MS because of an executive/frontal-related deficit. Individuals with MS are generally aware of these deficits and their negative impact on everyday life, so the development of strategies to alleviate such deficits seems of paramount importance. Thus, in the second part, I present the main outcomes of a cognitive intervention developed by our research group, which has been specifically designed to alleviate autobiographical memory and future thinking impairments in individuals with MS. The implications of these findings for neuropsychological care and well-being of individuals with MS are discussed in the final section, with an emphasis on the functional role of autobiographical memory and future thinking in various domains, including personal identity.

Antenatal exposure to solar radiation and learning disabilities: Population cohort study of 422,512 children.

Learning disability varies by month of conception. The underlying mechanism is unknown but vitamin D, necessary for normal brain development, is commonly deficient over winter in high latitude countries due to insufficient ultraviolet radiation. We linked the 2007-2016 Scottish School Pupil Censuses to Scottish maternity records and to sunshine hours and antenatal ultraviolet A/B radiation exposure derived from weather stations and satellites respectively. Logistic regression analyses were used to explore the associations between solar radiation, then ultraviolet B, and learning disabilities, adjusting for the potential confounding effects of month of conception and sex. Of the 422,512 eligible, singleton schoolchildren born at term in Scotland, 79,616 (18.8%) had a learning disability. Total antenatal sunshine hours (highest quintile; adjusted OR 0.89; 95% CI: 0.86, 0.93; p < 0.001) and ultraviolet B exposure (highest quintile; adjusted OR 0.55; 95% CI: 0.51, 0.60; p < 0.001) were inversely associated with learning disabilities with evidence of a dose-relationship. The latter association was independent of ultraviolet A exposure. Significant associations were demonstrated for exposure in all three trimesters. Low maternal exposure to ultraviolet B radiation may play a role in the seasonal patterning of learning disabilities. Further studies are required to corroborate findings and determine the effectiveness of supplements.

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.

Sketch and Speak: An Expository Intervention Using Note-Taking and Oral Practice for Children With Language-Related Learning Disabilities.

Purpose This preliminary study investigated an intervention procedure employing 2 types of note-taking and oral practice to improve expository reporting skills. Procedure Forty-four 4th to 6th graders with language-related learning disabilities from 9 schools were assigned to treatment or control conditions that were balanced for grade, oral language, and other features. The treatment condition received 6 30-min individual or pair sessions from the school of speech-language pathologists (SLPs). Treatment involved reducing statements from grade-level science articles into concise ideas, recording the ideas as pictographic and conventional notes, and expanding from the notes into full oral sentences that are then combined into oral reports. Participants were pretested and posttested on taking notes from grade-level history articles and using the notes to give oral reports. Posttesting also included written reports 1 to 3 days following the oral reports. Results The treatment group showed significantly greater improvement than the control group on multiple quality features of the notes and oral reports. Quantity, holistic oral quality, and delayed written reports were not significantly better. The SLPs reported high levels of student engagement and learning of skills and content within treatment. They attributed the perceived benefits to the elements of simplicity, visuals, oral practice, repeated opportunities, and visible progress. Conclusion This study indicates potential for Sketch and Speak to improve student performance in expository reporting and gives direction for strengthening and further investigating this novel SLP treatment. Supplemental Material https://doi.org/10.23641/asha.7268651.

Influence of Chronic Coenzyme Q10 Supplementation on Cognitive Function, Learning, and Memory in Healthy and Diabetic Middle-Aged Rats.

Diabetes mellitus can induce impairment in learning and memory. Cognitive and memory deficits are common in older adults and especially in those with diabetes. This is mainly because of hyperglycemia, oxidative stress, and vascular abnormalities. Coenzyme Q10 (CoQ10) can decrease oxidative stress, hyperglycemia, and inflammatory markers, and improve vascular function. Therefore, the aim of the present study was to investigate the possible effects of CoQ10 on cognitive function, learning, and memory in middle-aged healthy and diabetic rats. Adult middle-aged male Wistar rats (390-460 g, 12-13 months old) were divided into 6 experimental groups. Diabetes was induced by a single i.p. injection of streptozotocin (60 mg/kg). CoQ10 (20 or 120 mg/kg, orally by gavage) was administered for 45 days. The cognitive function and learning memory of rats were evaluated using novel object recognition (NOR) and passive avoidance tests. The discrimination index of the NOR test in the diabetic groups receiving CoQ10 (20 or 120 mg/kg) and the healthy group receiving CoQ10 (120 mg/kg) was significantly higher than that in the control group. In addition, the step through latency was significantly longer and the time spent in the dark compartment was significantly shorter in the diabetic groups receiving CoQ10 than in the control group. CoQ10 supplementation can improve learning and memory deficits induced by diabetes in older subjects. In addition, CoQ10 at higher doses can improve cognitive performance in older healthy subjects.

Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats.

Background The amygdala plays a key role in fear learning and extinction and has emerged as an important node of emotional-affective aspects of pain and pain modulation. Impaired fear extinction learning, which involves prefrontal cortical control of amygdala processing, has been linked to neuropsychiatric disorders. Here, we tested the hypothesis that fear extinction learning ability can predict the magnitude of neuropathic pain. Results We correlated fear extinction learning in naive adult male rats with sensory and affective behavioral outcome measures (mechanical thresholds, vocalizations, and anxiety- and depression-like behaviors) before and after the induction of the spinal nerve ligation model of neuropathic pain compared to sham controls. Auditory fear conditioning, extinction learning, and extinction retention tests were conducted after baseline testing. All rats showed increased freezing responses after fear conditioning. During extinction training, the majority (75%) of rats showed a decline in freezing level to 50% in 5 min (fear extinction+), whereas 25% of the rats maintained a high freezing level (>50%, fear extinction-). Fear extinction- rats showed decreased open-arm preference in the elevated plus maze, reflecting anxiety-like behavior, but there were no significant differences in sensory thresholds, vocalizations, or depression-like behavior (forced swim test) between fear extinction+ and fear extinction- types. In the neuropathic pain model (four weeks after spinal nerve ligation), fear extinction- rats showed a greater increase in vocalizations and anxiety-like behavior than fear extinction+ rats. Fear extinction- rats, but not fear extinction+ rats, also developed depression-like behavior. Extracellular single unit recordings of amygdala (central nucleus) neurons in behaviorally tested rats (anesthetized with isoflurane) found greater increases in background activity, bursting, and evoked activity in fear extinction- rats than fear extinction+ rats in the spinal nerve ligation model compared to sham controls. Conclusion The data may suggest that fear extinction learning ability predicts the magnitude of neuropathic pain-related affective rather than sensory behaviors, which correlates with differences in amygdala activity changes.

Scutellarin Ameliorates Learning and Memory Deficit via Suppressing ß-Amyloid Formation and Microglial Activation in Rats with Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion is considered as a pivotal factor of cognitive impairment that occurs in cerebrovascular diseases. This study investigated the ameliorating effect of scutellarin (SCT) on spatial cognitive impairment and ß-amyloid (Aß) formation in rats with chronic cerebral hypoperfusion induced by permanent bilateral common carotid artery occlusion (pBCAO). SCT is a flavonoid in medicinal herb of Erigeron breviscapus (vant.) Hand. Mazz. known to have neuroprotective, antioxidative and anti-inflammatory effects. However, the beneficial effect and pivotal mechanism of SCT on cognitive impairment are still unclear. SCT was treated orally with two doses (10 or 30 mg/kg) for 4 weeks. Results of Morris water maze test performed on the ninth week after pBCAO revealed that SCT (30 mg/kg)-treated rats had significantly shortened escape latencies in acquisition training trials, significantly prolonged swimming time at the platform and its surrounding zone, significant increase in memory score, significant reduction in the number of target heading, and significant reduction in the time required for the first target heading during the retention trial compared to rats in the sham-control group. SCT significantly inhibited the production of Aß(1-40) and Aß(1­42) in brain tissues. However, SCT significantly upregulated the expression levels of amyloid precursor protein and ß-site APP-converting enzyme-1 in the hippocampus. In addition, SCT significantly inhibited the activation of Iba1-expressing microglia in brain tissues. The results suggest that SCT can exert ameliorating effect on spatial cognitive impairment caused by chronic cerebral hypoperfusion through suppressing Aß formation and microglial activation in brain tissues. Therefore, SCT can be used as a beneficial drug for vascular dementia and Alzheimer's disease.

Absence of associative motor learning and impaired time perception in a rare case of complete cerebellar agenesis.

Primary cerebellar agenesis (PCA), a brain disease where the cerebellum does not develop, is an extremely rare congenital disease with only eleven living cases reported thus far. Studies of the PCA case will thus provide valuable insights into the necessity of cerebellar development for controlling and modulating cognitive functions of the brain. In this follow-up study, we further investigated the performance of associative learning and time perception of a 26-year-old female complete PCA case. We assessed whether delayed eyeblink conditioning (EBC), which represents prototypical associative motor learning function of the cerebellum, could be partially compensated by the extracerebellar brain regions in complete absence of the cerebellum. We also assessed whether the cerebellum, a critical brain region for millisecond-range interval timing, is essential for perception of the second-range time interval. Twelve neurotypical age-matched individuals were used as controls. We found that although the complete PCA patient had only mild to moderate motor deficits, she was unable to perform the delayed EBC even after 1-week of extensive training. Additionally, the PCA patient also performed poorly during time reproduction experiments in which she overproduced the millisecond-range time intervals, while underproduced the second-range time intervals. The PCA patient also failed to perform the temporal eyeblink conditioning with a 5 s fixed interval as the conditioned stimulus. These results indicate that the cerebellum is indispensable for associative motor learning and involved in timing of sub-second intervals, as well as in the perception of second-range intervals.

Retained capacity for perceptual learning of degraded speech in primary progressive aphasia and Alzheimer's disease.

BACKGROUND: Processing of degraded speech is a promising model for understanding communication under challenging listening conditions, core auditory deficits and residual capacity for perceptual learning and cerebral plasticity in major dementias. METHODS: We compared the processing of sine-wave-degraded speech in 26 patients with primary progressive aphasia (non-fluent, semantic, and logopenic variants), 10 patients with typical Alzheimer's disease and 17 healthy control subjects. Participants were required to identify sine-wave words that were more predictable (three-digit numbers) or less predictable (place names). The change in identification performance within each session indexed perceptual learning. Neuroanatomical associations of degraded speech processing were assessed using voxel-based morphometry. RESULTS: Patients with non-fluent and logopenic progressive aphasia and typical Alzheimer's disease showed impaired identification of sine-wave numbers, whereas all syndromic groups showed impaired identification of sine-wave place names. A significant overall identification advantage for numbers over place names was shown by patients with typical Alzheimer's disease, patients with semantic progressive aphasia and healthy control participants. All syndromic groups showed spontaneous perceptual learning effects for sine-wave numbers. For the combined patient cohort, grey matter correlates were identified across a distributed left hemisphere network extending beyond classical speech-processing cortices. CONCLUSIONS: These findings demonstrate resilience of auditory perceptual learning capacity across dementia syndromes, despite variably impaired perceptual decoding of degraded speech and reduced predictive integration of semantic knowledge. This work has implications for the neurobiology of dynamic sensory processing and plasticity in neurodegenerative diseases and for development of novel biomarkers and therapeutic interventions.

Different concentrations of docosahexanoic acid supplement during lactation result in different outcomes in preterm Sprague-Dawley rats.

PROPOSE: In this study, we evaluated the effects of different concentrations of docosahexanoic acid (DHA) supplement on preterm Sprague-Dawley rat pups, and in parallel, measured the phosphorylation activity of the mTOR pathway in the hippocampal CA1 area. METHODS: Preterm Sprague-Dawley rat pups were randomly assigned to experimental groups which included; a sufficient DHA group (100 mg/kg/day); an enriched DHA group (300 mg/kg/day); an excess DHA group (800 mg/kg/day); and a deficient DHA group (normal saline gavage 0.1 ml/10 g). Body weight (g) was measured at days 1/7/14/21/28/42, respectively. Spatial learning and memory were also tested using the Morris water maze at week 6 (day 42). Finally, activation of the mTOR signaling pathway in hippocampal CA1 area were evaluated by western blotting. RESULTS: Postnatal sufficient/enriched docosahexanoic acid supplement ameliorated body weight restriction, spatial learning and memory restriction, and decreased phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. Furthermore, excess docosahexanoic acid supplement impeded weight gain and spatial learning and memory, perturbed serum unsaturated fatty acid, and downregulated phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. CONCLUSION: Postnatal sufficient/enriched DHA supplement ameliorated growth and spatial learning and memory impairment and upregulated the mTOR pathway in preterm pups, although excessive DHA supplement did not have any beneficial effects.

Influences of early child nutritional status and home learning environment on child development in Vietnam.

Early childhood development plays a key role in a child's future health, educational success, and economic status. However, suboptimal early development remains a global challenge. This study examines the influences of quality of the home learning environment (HOME) and child stunting in the first year of life on child development. We used data collected from a randomized controlled trial of preconceptional micronutrient supplementation in Vietnam (n = 1,458). The Bayley Scales of Infant Development-III were used to assess cognition, language, and motor development domains at 2 years. At 1 year, 14% of children were stunted, and 15%, 58%, and 28% of children lived in poor, medium, and high HOME environments, respectively. In multivariate generalized linear regression models, living in a high HOME environment was significantly associated with higher scores (0.10 to 0.13 SD) in each of the developmental domains. Stunted children scored significantly lower for cognitive, language, and motor development (-0.11 to -0.18), compared to nonstunted children. The negative associations between stunting on development were modified by HOME; the associations were strong among children living in homes with a poor learning environment whereas they were nonsignificant for those living in high-quality learning environments. In conclusion, child stunting the first year of life was negatively associated with child development at 2 years among children in Vietnam, but a high-quality HOME appeared to attenuate these associations. Early interventions aimed at improving early child growth as well as providing a stimulating home environment are critical to ensure optimal child development.

n-3 Polyunsaturated fatty acid supplementation restored impaired memory and GABAergic synaptic efficacy in the hippocampus of stressed rats.

While chronic stress induces dendritic atrophy in the hippocampus and impairs learning and memory, supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) is known to improve learning and memory of control rats. Whether n-3 PUFA supplementation improves dendritic morphology, synaptic transmission, and memory of chronically stressed rats remains unknown. In this work, we randomly assigned male Sprague-Dawley rats in four experimental groups: two unsupplemented groups, control and stress, and two supplemented groups with n-3 PUFA (DHA and EPA mix), control + n-3 PUFA and stress + n-3 PUFA. Dendritic morphology and synaptic transmission in the hippocampus were evaluated by Golgi stain and patch-clamp tools, respectively. The Y-maze and Morris water maze were used to analyze the effects of chronic stress on memory. Supplementation with n-3 PUFA improved dendritic architecture and restored the frequency of inhibitory post-synaptic currents of hippocampal pyramidal neurons of rats from stress group. In addition, n-3 PUFA supplementation improved spatial memory. Our results demonstrate that n-3 PUFA supplementation had three beneficial effects on stressed rats: prevented or compensated dendritic atrophy in CA3; restored the probability of GABA release in CA1; and improved spatial memory. We argue that n-3 PUFA supplementation can be used in treating stress-related psychiatric disorders such as depression and anxiety.

Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model. Beginning from day 100, mice were treated with deferiprone (DFP), a ferric chelator that is able to cross the blood-brain barrier and is currently used in clinics as treatment for hemosiderosis. Our paradigm resulted in an impairment of the learning abilities in the rotarod task and the novel object recognition test. DFP treatment significantly improved the performance in both tasks. Although this was not accompanied by alterations in aSyn aggregation, our results support DFP as possible therapeutic option in PD.

Rosmarinic acid protects against chronic ethanol-induced learning and memory deficits in rats.

OBJECTIVES: Ethanol consumption induces neurological disorders including cognitive dysfunction. Oxidative damage is considered a likely cause of cognitive deficits. We aimed to investigate the effects of rosmarinic acid (RA) in different doses for 30 days on chronic ethanol-induced cognitive dysfunction using the passive avoidance learning (PAL) and memory task in comparison with donepezil, a reference drug. We also evaluated the levels of superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation in hippocampus as possible mechanisms. METHODS: Memory impairment was induced by 15% w/v ethanol (2 g/kg, i.g.) administration for 30 days. RA (8, 16, and 32 mg/kg, i.g.) or donepezil (2 mg/kg, i.g.) was administered 30 minutes before ethanol. The acquisition trial was done 1 hour after the last administration of RA and donepezil. At the end, animals were weighed and hippocami were isolated for analyzing of oxidant/antioxidant markers. RESULTS: Ethanol caused cognition deficits in the PAL and memory task. While RA 16 and 32 mg/kg improved cognition in control rats, it prevented learning and memory deficits of alcoholic groups. RA 8 mg/kg did not influence cognitive function in both control and alcoholic rats. RA 32 mg/kg had comparable effects with donepezil in prevention of acquisition and retention memory impairment. The higher doses of RA not only prevented increased lipid peroxidation and nitrite content but also decreased SOD, CAT, GSH, and FRAP levels in alcoholic groups and exerted antioxidant effects in non-alcoholic rats. DISCUSSION: We showed that RA administration dose-dependently prevented cognitive impairment induced by chronic ethanol in PAL and memory and disturbed oxidant/antioxidant status as a possible mechanism. The antioxidant, anticholinesterase, and neuroprotective properties of RA may be involved in the observed effects. Therefore, RA represents a potential therapeutic option against chronic ethanol-induced amnesia which deserves consideration and further examination.

The effects of Nigella sativa extract on hypothyroidism-associated learning and memory impairment during neonatal and juvenile growth in rats.

OBJECTIVES: It has been shown that hypothyroidism-induced oxidative damage in brain tissue is involved in its adverse effects on learning and memory. Nigella sativa (N. sativa) has been suggested to have antioxidant and neuroprotective effects. The objective of this study was to investigate the effects of hydroalcoholic extract of N. sativa on hypothyroidism-associated learning and memory impairment during neonatal and juvenile growth in rats. METHODS: Thirty pregnant rats were kept in separate cages. After delivery, the mothers and their offspring were randomly divided into six groups including: (1) control, (2) PTU (propylthiouracil), (3) PTU-NS 100, (4) PTU-NS 200, (5) PTU-NS 400, and (6) PTU-Vit C (vitamin C). All dams except the control group received 0.005% PTU in their drinking water during lactation. Besides PTU, dams in groups 3, 4, 5, and 6 received 100, 200, and 400 mg/kg N. sativa extract, or 100 mg/kg Vit C, respectively. After lactation period, pups continued to receive same experimental treatment for the first 8 weeks of their life. Then, 10 male offspring of each group were randomly selected and assessed for the learning and memory abilities by using Morris water maze (MWM) and passive avoidance (PA) tests. Blood samples were collected for thyroxine assessment, animals were euthanized, and the brain tissues were removed and analyzed for total thiol groups and malondialdehyde (MDA) concentrations. RESULTS: PTU exposure significantly increased the time latency in MWM test, while reduced the time spent in target quadrant, and decreased the latency for entering the dark compartment in PA test. These effects were associated with significant reduction in serum thyroxine levels and brain levels of thiol groups, and significant elevation in hippocampal MDA. Administration of 400 mg/kg N. sativa extract and 100 mg/kg Vit C reduced the time latency, while increased the time spent in target quadrant compared to the PTU group in MWM test. Treatment by 100-400 mg/kg of N. sativa extract and also Vit C significantly increased the time latency for entering the dark compartment in PA test. The serum thyroxine concentrations of the animals treated by all doses of the N. sativa extract as well as by Vit C were higher than that of the PTU group. Two hundred and four hundred milligrams/kilogram of NS extract and 100 mg/kg Vit C decreased the MDA concentration in hippocampal tissues, while increased thiol contents compared to the PTU group. DISCUSSION: The results of this study demonstrate that the hydroalcoholic extract of N. sativa have protective effects on hypothyroidism-associated learning and memory impairment during neonatal and juvenile growth in rats. The effects were comparable to Vit C and might be due to the protective effects of N. sativa extract against brain tissues' oxidative damage.

Thymol improves high-fat diet-induced cognitive deficits in mice via ameliorating brain insulin resistance and upregulating NRF2/HO-1 pathway.

The impaired insulin signaling has been recognized as a common pathogenetic mechanism between diabetes and Alzheimer's disease (AD). In the progression of AD, brain is characterized by defective insulin receptor substrate-1 (IRS-1) and increased oxidative stress. Thymol, a monoterpene phenol isolated from medicinal herbs, has exhibited robust neuroprotective effects. The present study was designed to investigate the protective effect of thymol on HFD-induced cognitive deficits, and explore the possible mechanisms. C57BL/6 J mice were fed for 12 weeks with either HFD or normal diet. The mice fed with HFD were dosed with metformin (200 mg/kg) or thymol (20, 40 mg/kg) daily. It was observed that thymol treatment significantly reversed the gain of body weight and peripheral insulin resistance induced by HFD. Meanwhile, thymol improved the cognitive impairments in the Morris Water Maze (MWM) test and decreased HFD-induced Aß deposition and tau hyperphosphorylation in the hippocampus, which may be correlated with the inhibition of hippocampal oxidative stress and inflammation. In addition, thymol down-regulated the level of P-Ser307 IRS-1, and hence enhancing the expression of P-Ser473 AKT and P-Ser9 GSK3ß. We further found that the protective effects of thymol on cognitive impairments were associated with the up-regulation of nuclear respiratory factor (Nrf2)/heme oxygenase-1(HO-1) pathway. In conclusion, thymol exhibited beneficial effects on HFD-induced cognitive deficits through improving hippocampal insulin resistance, and activating Nrf2/HO-1 signaling.

Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits.

OBJECTIVE: Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. METHODS: A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. RESULTS: Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits. SIGNIFICANCE: This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

Effects of caffeic acid on learning deficits in a model of Alzheimer's disease.

Caffeic acid is a type of phenolic acid and organic acid. It is found in food (such as tomatoes, carrots, strawberries, blueberries and wheat), beverages (such as wine, tea, coffee and apple juice) as well as Chinese herbal medicines. In the present study, we examined the effects of caffeic acid on learning deficits in a rat model of Alzheimer's disease (AD). The rats were randomly divided into three groups: i) control group, ii) AD model group and iii) caffeic acid group. Caffeic acid significantly rescued learning deficits and increased cognitive function in the rats with AD as demonstrated by the Morris water maze task. Furthermore, caffeic acid administration resulted in a significant decrease in acetylcholinesterase activity and nitrite generation in the rats with AD compared with the AD model group. Furthermore, caffeic acid suppressed oxidative stress, inflammation, nuclear factor­κB­p65 protein expression and caspase­3 activity as well as regulating the protein expression of p53 and phosphorylated (p-)p38 MAPK expression in the rats with AD. These experimental results indicate that the beneficial effects of caffeic acid on learning deficits in a model of AD were due to the suppression of oxidative stress and inflammation through the p38 MAPK signaling pathway.

Sideritis spp. Extracts Enhance Memory and Learning in Alzheimer's ß-Amyloidosis Mouse Models and Aged C57Bl/6 Mice.

Nowadays, Alzheimer's disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-ß (Aß) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard to their effects on cognition in APP-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aß deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in APP-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aß42 load in APP-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α-secretase ADAM10. Moreover, the treatment was able to fully rescue neuronal loss of APP-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer's disease by affecting its most prominent hallmarks: Aß pathology and cognitive decline.