The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

OBJECTIVE: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. METHODS: Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. RESULTS: Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. CONCLUSIONS: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Herbal Medicine for Slowing Aging and Aging-associated Conditions: Efficacy, Mechanisms and Safety.

Aging and aging-associated diseases are issues with unsatisfactory answers in the medical field. Aging causes important physical changes which, even in the absence of the usual risk factors, render the cardiovascular system prone to some diseases. Although aging cannot be prevented, slowing down the rate of aging is entirely possible to achieve. In some traditional medicine, medicinal herbs such as Ginseng, Radix Astragali, Ganoderma lucidum, Ginkgo biloba, and Gynostemma pentaphyllum are recognized by the "nourishing of life" and their role as anti-aging phytotherapeutics is increasingly gaining attention. By mainly employing PubMed here we identify and critically analysed 30 years of published studies focusing on the above herbs' active components against aging and aging-associated conditions. Although many plant-based compounds appear to exert an anti-aging effect, the most effective resulted in being flavonoids, terpenoids, saponins, and polysaccharides, which include astragaloside, ginkgolide, ginsenoside, and gypenoside specifically covered in this review. Their effects as antiaging factors, improvers of cognitive impairments, and reducers of cardiovascular risks are described, as well as the molecular mechanisms underlying the above-mentioned effects along with their potential safety. Telomere and telomerase, PPAR-α, GLUTs, FOXO1, caspase-3, bcl-2, along with SIRT1/AMPK, PI3K/Akt, NF-κB, and insulin/insulin-like growth factor-1 pathways appear to be their preferential targets. Moreover, their ability to work as antioxidants and to improve the resistance to DNA damage is also discussed. Although our literature review indicates that these traditional herbal medicines are safe, tolerable, and free of toxic effects, additional well-designed, large-scale randomized control trials need to be performed to evaluate short- and long-term effects and efficacy of these medicinal herbs.

Combination of chick embryo and nutrient mixture prevent D-galactose-induced cognitive deficits, immune impairment and oxidative stress in aging rat model.

Aging is spontaneous and inevitable processes that lead to changes in biological systems. The present paper was designed to investigate the anti-aging roles of chick embryo (CE) and nutrient mixture (NM) in aging rats. Aging was induced by administration of D-galactose (D-gal, 500 mg/kg/day for 90 days). CE and NM were administered to aging rats through different dose gavage once a day. Cognitive function assessment was performed using the Morris water maze test. At the end of experiment, serum and tissues were collected for immunity and antioxidation function. The organs and tissues were excised for histological study. The results demonstrated that CE plus NM was superior treatment to improve the histopathologic changes and reverse learning and memory impairment of the aging rats. CE plus NM also increased the spleen and thymus index as well as splenocyte proliferation, and reversed inflammatory cytokine levels. In addition, the biochemical index showed that CE plus NM could improve the antioxidant enzyme activity of the aging rats, decrease lipofuscin (LF) and glutamate content. CE plus NM also inhibited the activation of TLR4/NF-κB pathway stimulated by LPS in splenic B lymphocytes. Overall, these results seem to be implying that CE plus NM was used as potentially natural supplement or functional food for preventing aging.

Protective Effects of 1-Methylnicotinamide on Aß1-42-Induced Cognitive Deficits, Neuroinflammation and Apoptosis in Mice.

The neurotoxicity of Aß peptides has been well documented, but effective neuroprotective approaches against Aß neurotoxicity are unavailable. In the present study, we investigated effects of 1-Methylnicotinamide (MNA), known as a main metabolite of nicotinamide (NA), on the impairment of learning and memory induced by Aß and the underlying mechanisms. We found that intragastric administration of MNA at 100 or 200 mg/kg for 3 weeks significantly reversed bilateral intrahippocampal injection of Aß1-42-induced cognitive impairments in the Morris water maze (MWM), Y-maze and Novel object recognition tests. Furthermore, MNA suppressed Aß1-42-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the expression of IL-6, TNF-α and nuclear translocation of NF-κB p65, as well as attenuated neuronal apoptosis as indicated by decreased TUNEL-positive cells and ratio of caspase-3 fragment to procaspase-3, and increased ratio of Bcl-2/Bax in the hippocampus. Our results show that MNA may ameliorate Aß1-42-induced cognition deficits, which is involved in inhibition of neuroinflammation and apoptosis mediated by NF-κB signaling, suggesting that MNA could have potential therapeutic value for AD. Graphical Abstract Neuroprotective affect of MNA on Aß1-42-induced cognitive deficits.

Reorganization of the somatosensory pathway after subacute incomplete cervical cord injury.

OBJECTIVE: The main purpose of the present study was to investigate the possible somatosensory-related brain functional reorganization after traumatic spinal cord injury (SCI). METHODS: Thirteen patients with subacute incomplete cervical cord injury (ICCI) and thirteen age- and sex-matched healthy controls (HCs) were recruited. Eleven patients and all the HCs underwent both sensory task-related brain functional scanning and whole brain structural scanning on a 3.0 Tesla MRI system, and two patients underwent only structural scanning; the process of structural scanning was completed on thirteen patients, while functional scanning was only applied to eleven patients. We performed sensory task-related functional MRI (fMRI) to investigate the functional changes in the brain. In addition, voxel-based morphometry (VBM) was applied to explore whether any sensory-related brain structural changes occur in the whole brain after SCI. RESULTS: Compared with HCs, ICCI patients exhibited decreased activation in the left postcentral gyrus (postCG), the brainstem (midbrain and right pons) and the right cerebellar lobules IV-VI. Moreover, a significant positive association was found between the activation in the left PostCG and the activation in both the brainstem and the right cerebellar lobules IV-VI. Additionally, the decrease in gray matter volume (GMV) was detected in the left superior parietal lobule (SPL). The decrease of white matter volume (WMV) was observed in the right temporal lobe, the right occipital lobe, and the right calcarine gyrus. No structural change in the primary sensory cortex (S1), the secondary somatosensory cortex (S2) or the thalamus was detected. CONCLUSION: These functional and structural findings may demonstrate the existence of an alternative pathway in the impairment of somatosensory function after SCI, which consists of the ipsilateral cerebellum, the brainstem and the contralateral postCG. It provides a new theoretical basis for the mechanism of sensory-related brain alteration in SCI patients and the rehabilitation therapy based on this pathway in the future.

Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery.

Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity α4ß2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity α7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials. IMPLICATIONS: The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.

Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research.

Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.

Sensorimotor stroke alters hippocampo-thalamic network activity.

Many stroke survivors experience persisting episodic memory disturbances. Since hippocampal and para-hippocampal areas are usually spared from the infarcted area, alterations of memory processing networks remote from the ischemic brain region might be responsible for the observed clinical symptoms. To pinpoint changes in activity of hippocampal connections and their role in post-stroke cognitive impairment, we induced ischemic stroke by occlusion of the middle cerebral artery (MCAO) in adult rats and analyzed the functional and structural consequences using activity-dependent manganese (Mn2+) enhanced MRI (MEMRI) along with behavioral and histopathological analysis. MCAO caused stroke lesions of variable extent along with sensorimotor and cognitive deficits. Direct hippocampal injury occurred in some rats, but was no prerequisite for cognitive impairment. In healthy rats, injection of Mn2+ into the entorhinal cortex resulted in distribution of the tracer within the hippocampal subfields into the lateral septal nuclei. In MCAO rats, Mn2+ accumulated in the ipsilateral thalamus. Histopathological analysis revealed secondary thalamic degeneration 28 days after stroke. Our findings provide in vivo evidence that remote sensorimotor stroke modifies the activity of hippocampal-thalamic networks. In addition to potentially reversible alterations in signaling of these connections, structural damage of the thalamus likely reinforces dysfunction of hippocampal-thalamic circuitries.

Beneficial Effects of the Calcium Channel Blocker CTK 01512-2 in a Mouse Model of Multiple Sclerosis.

Voltage-gated calcium channels (VGCCs) play a critical role in neuroinflammatory diseases, such as multiple sclerosis (MS). CTK 01512-2 is a recombinant version of the peptide Phα1ß derived from the spider Phoneutria nigriventer, which inhibits N-type VGCC/TRPA1-mediated calcium influx. We investigated the effects of this molecule in the mouse model of experimental autoimmune encephalomyelitis (EAE). The effects of CTK 01512-2 were compared to those displayed by ziconotide-a selective N-type VGCC blocker clinically used for chronic pain-and fingolimod-a drug employed for MS treatment. The intrathecal (i.t.) treatment with CTK 01512-2 displayed beneficial effects, by preventing nociception, body weight loss, splenomegaly, MS-like clinical and neurological scores, impaired motor coordination, and memory deficits, with an efficacy comparable to that observed for ziconotide and fingolimod. This molecule displayed a favorable profile on EAE-induced neuroinflammatory changes, including inflammatory infiltrate, demyelination, pro-inflammatory cytokine production, glial activation, and glucose metabolism in the brain and spinal cord. The recovery of spatial memory, besides a reduction of serum leptin levels, allied to central and peripheral elevation of the anti-inflammatory cytokine IL-10, was solely modulated by CTK 01512-2, dosed intrathecally. The intravenous (i.v.) administration of CTK 01512-2 also reduced the EAE-elicited MS-like symptoms, similarly to that seen in animals that received fingolimod orally. Ziconotide lacked any significant effect when dosed by i.v. route. Our results indicate that CTK 01512-2 greatly improved the neuroinflammatory responses in a mouse model of MS, with a higher efficacy when compared to ziconotide, pointing out this molecule as a promising adjuvant for MS management.

Response to Targeted Cognitive Training Correlates with Change in Thalamic Volume in a Randomized Trial for Early Schizophrenia.

Reduced thalamic volume is consistently observed in schizophrenia, and correlates with cognitive impairment. Targeted cognitive training (TCT) of auditory processing in schizophrenia drives improvements in cognition that are believed to result from functional neuroplasticity in prefrontal and auditory cortices. In this study, we sought to determine whether response to TCT is also associated with structural neuroplastic changes in thalamic volume in patients with early schizophrenia (ESZ). Additionally, we examined baseline clinical, cognitive, and neural characteristics predictive of a positive response to TCT. ESZ patients were randomly assigned to undergo either 40 h of TCT (N=22) or a computer games control condition (CG; N=22 s). Participants underwent MRI, clinical, and neurocognitive assessments before and after training (4-month interval). Freesurfer automated segmentation of the subcortical surface was carried out to measure thalamic volume at both time points. Left thalamic volume at baseline correlated with baseline global cognition, while a similar trend was observed in the right thalamus. The relationship between change in cognition and change in left thalamus volume differed between groups, with a significant positive correlation in the TCT group and a negative trend in the CG group. Lower baseline symptoms were related to improvements in cognition and left thalamic volume preservation following TCT. These findings suggest that the cognitive gains induced by TCT in ESZ are associated with structural neuroplasticity in the thalamus. Greater symptom severity at baseline reduced the likelihood of response to TCT both with respect to improved cognition and change in thalamic volume.

Impaired Cognitive Function after Perineuronal Net Degradation in the Medial Prefrontal Cortex.

Perineuronal nets (PNNs) are highly organized components of the extracellular matrix that surround a subset of mature neurons in the CNS. These structures play a critical role in regulating neuronal plasticity, particularly during neurodevelopment. Consistent with this role, their presence is associated with functional and structural stability of the neurons they ensheath. A loss of PNNs in the prefrontal cortex (PFC) has been suggested to contribute to cognitive impairment in disorders such as schizophrenia. However, the direct consequences of PNN loss in medial PFC (mPFC) on cognition has not been demonstrated. Here, we examined behavior after disruption of PNNs in mPFC of Long-Evans rats following injection of the enzyme chondroitinase ABC (ChABC). Our data show that ChABC-treated animals were impaired on tests of object oddity perception. Performance in the cross-modal object recognition (CMOR) task was not significantly different for ChABC-treated rats, although ChABC-treated rats were not able to perform above chance levels whereas control rats were. ChABC-treated animals were not significantly different from controls on tests of prepulse inhibition (PPI), set-shifting (SS), reversal learning, or tactile and visual object recognition memory. Posthumous immunohistochemistry confirmed significantly reduced PNNs in mPFC due to ChABC treatment. Moreover, PNN density in the mPFC predicted performance on the oddity task, where higher PNN density was associated with better performance. These findings suggest that PNN loss within the mPFC impairs some aspects of object oddity perception and recognition and that PNNs contribute to cognitive function in young adulthood.

Subcortical gray matter atrophy is associated with cognitive deficit in multiple sclerosis but not in systemic lupus erythematosus patients.

Cognitive impairment is a significant clinical problem both in multiple sclerosis (MS) and systemic lupus erythematosus (SLE) patients. In MS cognitive dysfunction has been associated with brain atrophy and total demyelinating lesion volume. In SLE cognitive impairment is much less understood, and its link to structural brain damage remains to be established. The aim of this study was to identify the relationship between subcortical gray matter volume and cognitive impairment in MS and SLE. We recruited 37 MS and 38 SLE patients matched by age, disease duration and educational level. Patients underwent magnetic resonance imaging (MRI) and a battery of psychometric tests. Severity of cognitive impairment was similar in both cohorts despite larger white matter lesion load in MS patients. Psychometric scores were associated with global and subcortical gray matter atrophy measures and lesion load in MS, but not in SLE. In SLE, the lack of a relationship between cognitive impairment and structural damage, defined either as atrophy or white matter lesions, indicates a different causal mechanism of cognitive deficit.

Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy.

The chemotherapy drug, 5-fluorouracil (5-FU), has been reported to cause cognitive impairments in cancer patients. The drug also reduces cell proliferation and survival in the brain. Asiatic acid (AA) is a triterpene compound found in Centella asiatica that can protect against reduction of neurogenesis in the hippocampus and memory deficits induced by valproic acid (VPA). In the present study, we investigated the preventive effects of AA on the deficits in spatial working memory and cell proliferation and survival caused by 5-FU chemotherapy in a rat model. Male Sprague Dawley rats received 5-FU (5 i.v. injections, 25 mg/kg) on day 8, 11, 14, 17 and 20 of the study. This was co-administered with AA (30 mg/kg, oral gavage tube) either 20 days before receiving 5-FU (preventive), after receiving 5-FU (recovery), or for the entire period of the experiment (throughout). Spatial working memory was determined using the novel object location (NOL) test and hippocampal cell proliferation and survival of dividing cells were quantified using immunohistochemistry. Rats in the 5-FU alone and recovery groups showed memory deficits in the NOL test and reductions in cell proliferation and cell survival in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Rats in the control, AA alone, and both preventive and throughout co-administration groups, however, did not exhibit these characteristics. The results showed that 5-FU chemotherapy impaired memory and reduced cell proliferation and cell survival in the SGZ of the hippocampal dentate gyrus. However, these impairments in the animals receiving 5-FU chemotherapy were restored to control levels when AA was co-administered before and during 5-FU treatment. These data demonstrate that AA can prevent the spatial working memory and hippocampal neurogenesis impairments caused by 5-FU chemotherapy.

Zeaxanthin improves diabetes-induced cognitive deficit in rats through activiting PI3K/AKT signaling pathway.

Published studies have shown that cognitive deficit is a characteristic manifestation of neurodegenerative disease in diabetes. However, there is no effective prevention and treatment for this diabetes-associated behavior disorder. In the present study, we attempted to elucidate the effect of zeaxanthin on cognitive deficit and the change in the hippocampus correlated with cognitive decline in diabetic rats. Diabetic rats in this study were induced by high-fat diet and low-dose streptozocin (STZ), cognitive ability of rats were evaluated use morris water maze (MWM) and morphology change in hippocampus was assessed by cresyl violet stain. Moreover, we detected the expression of phosphorylated serine/threonine kinase (p-AKT) and Cleaved caspase-3, and the activity of nuclear factor-κB (NF-κB) use western-blot (WB). Results displayed that supplementation with zeaxanthin reduce blood glucose, improve cognitive deficit, survive neural cell, increase p-AKT level, inhibit Cleaved caspase-3 level and NF-κB nuclear transcription in hippocampus. This study demonstrated that zeaxanthin ameliorate diabetes-related cognitive deficit may by means of protecting neural cell from hyperglycemia involved in AKT/NF-κB signaling pathway. This study may provide a potential therapeutic approach for the prevention of diabetes- associated cognitive deficit.

Hypothalamic hamartoma: Neuropathology and epileptogenesis.

Hypothalamic hamartomas (HHs) are congenital malformations of the ventral hypothalamus resulting in treatment-resistant epilepsy and are intrinsically epileptogenic for the gelastic seizures that are the hallmark symptom of this disorder. This paper reviews the neuropathologic features of HHs associated with epilepsy, with an emphasis on characterizing neuron phenotypes and an ultimate goal of understanding the cellular model of ictogenesis occurring locally within this tissue. We also present previously unpublished findings on Golgi staining of HH. The microarchitecture of HH is relatively simple, with nodular clusters of neurons that vary in size and abundance with poorly defined boundaries. Approximately 80-90% of HH neurons have an interneuron-like phenotype with small, round soma and short, unbranched processes that lack spines. These neurons express glutamic acid decarboxylase and likely utilize γ-aminobutyric acid (GABA) as their primary neurotransmitter. They have intrinsic membrane properties that lead to spontaneous pacemaker-like firing activity. The remaining HH neurons are large cells with pleomorphic, often pyramidal, soma and dendrites that are more likely to be branched and have spines. These neurons appear to be excitatory, projection-type neurons, and have the functionally immature behavior of depolarizing and firing in response to GABA ligands. We hypothesize that the irregular neuronal clusters are the functional unit for ictogenesis. Further research to define and characterize these local networks is required to fully understand the cellular mechanisms responsible for gelastic seizures.

Association between tea consumption and risk of cognitive disorders: A dose-response meta-analysis of observational studies.

BACKGROUND: The epidemiological evidence for a dose-response relationship between tea consumption and risk of cognitive disorders is sparse. The aim of the study was to summarize the evidence for the association of tea consumption with risk of cognitive disorders and assess the dose-response relationship. METHODS: We searched electronic databases of Pubmed, Embase, and Cochrane Library (from 1965 to Jan 19, 2017) for eligible studies that published in the international journals. A random-effects model was used to pool the most adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). RESULTS: Seventeen studies involving 48,435 participants were included in our study. The meta-analysis showed that a higher tea consumption was associated with a significant reduction in the risk of cognitive disorders (OR=0.73, 95% CI: 0.65-0.82). When considering the specific types of tea consumption, the significantly inverse association is only found in green tea consumption (OR=0.64, 95% CI: 0.53-0.77) but not in black/oolong tea consumption (OR=0.75, 95% CI: 0.55-1.01). Dose-response meta-analysis indicated that tea consumption is linearly associated with a reduced risk of cognitive disorders. An increment of 100 ml/day, 300 ml/day, and 500 ml/day of tea consumption was associated with a 6% (OR=0.94, 95% CI: 0.92-0.96), 19% (OR=0.81, 95% CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82) lower risk of cognitive disorders. CONCLUSIONS: Tea consumption is inversely and linearly related to the risk of cognitive disorders. More studies are needed to further confirm our findings.

Abnormal subcortical nuclei shapes in patients with type 2 diabetes mellitus.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) increases the risk of brain atrophy and dementia. We aimed to elucidate deep grey matter (GM) structural abnormalities and their relationships with T2DM cognitive deficits by combining region of interest (ROI)-based volumetry, voxel-based morphometry (VBM) and shape analysis. METHODS: We recruited 23 T2DM patients and 24 age-matched healthy controls to undergo T1-weighted structural MRI scanning. Images were analysed using the three aforementioned methods to obtain deep GM structural shapes and volumes. Biochemical and cognitive assessments were made and were correlated with the resulting metrics. RESULTS: Shape analysis revealed that T2DM is associated with focal atrophy in the bilateral caudate head and dorso-medial part of the thalamus. ROI-based volumetry only detected thalamic volume reduction in T2DM when compared to the controls. No significant between-group differences were found by VBM. Furthermore, a worse performance of cognitive processing speed correlated with more severe GM atrophy in the bilateral dorso-medial part of the thalamus. Also, the GM volume in the bilateral dorso-medial part of the thalamus changed negatively with HbA1c. CONCLUSIONS: Shape analysis is sensitive in identifying T2DM deep GM structural abnormalities and their relationships with cognitive impairments, which may greatly assist in clarifying the neural substrate of T2DM cognitive dysfunction. KEY POINTS: • Type 2 diabetes mellitus is accompanied with brain atrophy and cognitive dysfunction • Deep grey matter structures are essential for multiple cognitive processes • Shape analysis revealed local atrophy in the dorso-medial thalamus and caudatum in patients • Dorso-medial thalamic atrophy correlated to cognitive processing speed slowing and high HbA1c. • Shape analysis has advantages in unraveling neural substrates of diabetic cognitive deficits.

Repeated Acute Oral Exposure to Cannabis sativa Impaired Neurocognitive Behaviours and Cortico-hippocampal Architectonics in Wistar Rats.

The most abused illicit drug in both the developing and the developed world is Cannabis disposing users to varying forms of personality disorders. However, the effects of cannabis on cortico-hippocampal architecture and cognitive behaviours still remain elusive.  The present study investigated the neuro-cognitive implications of oral cannabis use in rats. Eighteen adult Wistar rats were randomly grouped to three. Saline was administered to the control rats, cannabis (20 mg/kg) to the experimental group I, while Scopolamine (1 mg/kg. ip) was administered to the last group as a standard measure for the cannabis induced cognitive impairment. All treatments lasted for seven consecutive days. Open Field Test (OFT) was used to assess locomotor activities, Elevated Plus Maze (EPM) for anxiety-like behaviour, and Y maze paradigm for spatial memory and data subjected to ANOVA and T test respectively. Thereafter, rats were sacrificed and brains removed for histopathological studies. Cannabis significantly reduced rearing frequencies in the OFT and EPM, and increased freezing period in the OFT. It also reduced percentage alternation similar to scopolamine in the Y maze, and these effects were coupled with alterations in the cortico-hippocampal neuronal architectures. These results point to the detrimental impacts of cannabis on cortico-hippocampal neuronal architecture and morphology, and consequently cognitive deficits.

Tanshinone IIA Attenuates Sevoflurane Neurotoxicity in Neonatal Mice.

BACKGROUND: Sevoflurane is the most widely used inhalational anesthetic in pediatric medicine. Despite this, sevoflurane has been reported to exert potentially neurotoxic effects on the developing brain. Clinical interventions and treatments for these effects are limited. Tanshinone IIA (Tan IIA), extracted from Salvia miltiorrhiza (Danshen), has been documented to alleviate cognitive decline in traditional applications. Therefore, we hypothesized that preadministration of Tan IIA may attenuate sevoflurane-induced neurotoxicity, suggesting that Tan IIA is a new and promising drug capable of counteracting the effects of cognitive dysfunction produced by general anesthetics. METHODS: To test this hypothesis, neonatal C57 mice (P6) were exposed to 3% sevoflurane for 2 hours with or without Tan IIA pretreatment at a dose of 10 mg/kg or 20 mg/kg for 3 consecutive days. Cognitive behavior tests such as open field tests and fear conditioning were performed to evaluate locomotor and cognitive function at P31 and P32. At P8, other separate tests, including TdT mediated dUTP Nick End Labeling (TUNEL) assay, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and electron microscopy, were performed. The mean differences among groups were compared using 1-way analysis of variance followed by Bonferroni post hoc multiple comparison tests. RESULTS: Repeated exposure to sevoflurane leads to significant cognitive impairment in mice, which may be explained by increased apoptosis, overexpression of neuroinflammatory markers, and changes in synaptic ultrastructure. Interestingly, preadministration of Tan IIA ameliorated these neurocognitive deficits, as shown by increased freezing percentages on the fear conditioning test (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, mean difference, 19, 99% confidence interval for difference, 6.4-31, P < .0001, n = 6). The treatment also reduced the percentage of TUNEL-positive nuclei (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 2.6, 0.73-4.5, P = .0004, n = 6) and the normalized expression of cleaved caspase-3 (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 0.27, 0.02-0.51, P = .0046, n = 5). Moreover, it attenuated the production of the neuroinflammatory mediators interleukin (IL)-1ß and IL-6 (normalized sevoflurane versus sevoflurane+Tan IIA [20 mg/kg]: IL-1ß: 0.75, 0.47-1.0; P < .0001; IL-6: 0.66, 0.35-0.97; P < .0001; n = 10 per group). Finally, based on measurements of postsynaptic density, the treatment preserved synaptic ultrastructure (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, 42, 20-66; P < .0001; n = 12 per group). CONCLUSIONS: These results indicate that Tan IIA can alleviate sevoflurane-induced neurobehavioral abnormalities and may decrease neuroapoptosis and neuroinflammation.

Effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits in the hippocampus of streptozotocin-induced type 1 diabetes mellitus rats.

Increasing evidence demonstrates an association between diabetes and hippocampal neuron damage. This study aimed to determine the effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits (GCLM and GCLC) in the hippocampus of streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. At 12weeks after streptozotocin injection, T1DM rats were randomly divided into 4 groups (n=15 each group) to receive no treatment (T1DM), saline (T1DM+saline), alpha-lipoic acid (T1DM+alpha-lipoic acid), and troxerutin (T1DM+troxerutin), respectively, for 6weeks. Meanwhile, 10 control animals (NC group) were assessed in parallel. Learning performance was evaluated by the Morris water maze. After treatment, hippocampi were collected for pathological examination by hematoxylin and eosin (H&E) staining. Next, hippocampal superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were assessed. Finally, glutamate cysteine ligase catalytic (GCLC) and glutamate cysteine ligase modifier (GCLM) subunit mRNA and protein levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Compared with T1DM and T1DM+saline groups, escape latency was overtly reduced in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Significantly increased GCLM and GCLC mRNA levels, GCLC protein amounts, SOD activity, and GSH levels, and reduced MDA amounts were observed in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. In T1DM and T1DM+saline groups, H&E staining showed less pyramidal cells in the hippocampus, with disorganized layers, karyopyknosis, decreased endochylema, and cavitation, effects relieved in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Troxerutin alleviates oxidative stress and promotes learning in streptozotocin-induced T1DM rats, a process involving GCLC expression.