Treatment Combining Focused Ultrasound with Gastrodin Alleviates Memory Deficit and Neuropathology in an Alzheimer’s Disease-Like Experimental Mouse Model

Alzheimer’s disease (AD) is the most common type of dementia but lacks effective treatment at present. Gastrodin (GAS) is a phenolic glycoside extracted from the traditional Chinese herb—Gastrodia elata—and has been reported as a potential therapeutic agent for AD. However, its efficiency is reduced for AD patients due to its limited BBB permeability. Studies have demonstrated the feasibility of opening the blood-brain barrier (BBB) via focused ultrasound (FUS) to overcome the obstacles preventing medicines from blood flow into the brain tissue. We explored the therapeutic potential of FUS-mediated BBB opening combined with GAS in an AD-like mouse model induced by unilateral intracerebroventricular (ICV) injection of Aβ1-42. Mice were divided into 5 groups: control, untreated, GAS, FUS and FUS+GAS. Combined treatment (FUS+GAS) rather than single intervention (GAS or FUS) alleviated memory deficit and neuropathology of AD-like mice. The time that mice spent in the novel arm was prolonged in the Y-maze test after 15-day intervention, and the waste-cleaning effect was remarkably increased. Contents of Aβ, tau, and P-tau in the observed (also the targeted) hippocampus were reduced. BDNF, synaptophysin (SYN), and PSD-95 were upregulated in the combined group. Overall, our results demonstrate that FUS-mediated BBB opening combined with GAS injection exerts the potential to alleviate memory deficit and neuropathology in the AD-like experimental mouse model, which may be a novel strategy for AD treatment.

Combined royal jelly 10-hydroxydecanoic acid and aspirin is synergistic against memory deficit and neuroinflammation

Alzheimer’s disease (AD), the most common form of neurodegenerative dementia among the older population, is associated with acute or chronic inflammation. As a nonsteroidal anti-inflammatory drug, aspirin has recently been...

Thymoquinone Improved Nonylphenol-Induced Memory Deficit and Neurotoxicity Through its Antioxidant and Neuroprotective Effects

Nonylphenol (NP), a well-known endocrine-disrupter chemical, has several harmful effects on the central nervous system including neuroendocrine disruption, cognitive impairment, and neurotoxicity. Thymoquinone (TQ) is a main bioactive compound in the black seeds of Nigella sativa that has antioxidant, anti-inflammatory, and neuroprotective properties. Here, we investigated the neuroprotective effect of TQ against NP-induced memory deficit and neurotoxicity in rats. To induce memory impairment, NP (25 mg/kg) was used as gavage in male Wistar rats for 21 days. TQ (2.5, 5 and 10mg/kg) was intraperitoneally administered in NP-treated animals. The morris water maze test was performed to assess spatial learning and memory. The hippocampal tissues were isolated from the brain for histopathological evaluation. Biochemical, molecular and cellular tests were performed to quantify oxidant (malondialdehyde; MDA)/antioxidant (superoxide dismutase (SOD), total antioxidant capacity (TAC) and reduced glutathione (GSH) parameters as well as markers for astrocytic activation (glial fibrillary acidic protein; GFAP) and neuronal death (alpha-synuclein; α-syn). Results showed TQ (5 mg/kg) significantly improved NP-induced memory impairment. Histological data revealed a significant increase in the number of necrotic cells in hippocampus, and TQ treatment markedly decreased this effect. The GSH and TAC levels were significantly increased in TQ-treated groups compared to NP group. The molecular analysis indicated that NP increased GFAP and decreased α-syn expression and TQ treatment did the reverse. In vitro study in astrocytes isolated from mice brain showed that TQ significantly increased cell viability in NP-induced cytotoxicity. This study strongly indicates that TQ has neuroprotective effects on NP-induced neurotoxicity through reducing oxidative damages and neuroinflammation.

Isolated Memory Loss in Anti-NMDAR Encephalitis

Background and ObjectivesTo report a case of anti-NMDAR encephalitis presenting with isolated memory dysfunction.MethodsA 29-year-old woman was admitted to the Neurology Department referring memory impairment with a subacute onset. The initial assessment included EEG, neuropsychological tests, and brain MRI. Serum and CSF samples were collected for immunologic studies. The diagnostic evaluation was completed with a total body PET scan.ResultsPatient's neurologic examination was unremarkable apart from an episodic memory deficit, confirmed by neuropsychological examination. The EEG revealed epileptiform discharges in the temporal lobes, whereas brain MRI showed bilateral temporal lobes hyperintense lesions on fluid-attenuated inversion recovery images and T2-weighted images. NMDAR-IgG was detected in the patient's serum and CSF by cell-based assay confirming the diagnosis of definite anti-NMDAR encephalitis. The total body PET showed only a slight hypometabolism in the right temporal cortex and in the cerebellar hemispheres. After a course of IV immunoglobulin and corticosteroid therapy, a marked improvement of the memory deficit was observed.DiscussionThis case shows that anti-NMDAR encephalitis can present with isolated memory loss. Neural antibody testing in these patients could play a pivotal role in early diagnosis and prompt treatment.

Preliminary comparative study of cortical thickness in HIV-infected patients with and without working memory deficit

Purpose Changes in cerebral cortical regions occur in HIV-infected patients, even in those with mild neurocognitive disorders. Working memory / attention is one of the most affected cognitive domain in these patients, worsening their quality of life. Our objective was to assess whether cortical thickness differs between HIV-infected patients with and without working memory deficit. Methods Forty-one adult HIV-infected patients with and without working memory deficit were imaged on a 1.5 T scanner. Working memory deficit was classified by composite Z scores for performance on the Digits and Letter-Number Sequencing subtests of the Wechsler Adult Intelligence Scale (third edition; WAIS-III). Cortical thickness was determined using FreeSurfer software. Differences in mean cortical thickness between groups, corrected for multiple comparisons using Monte-Carlo simulation, were examined using the query design estimate contrast tool of the FreeSurfer software. Results Greater cortical thickness in left pars opercularis of the inferior frontal gyrus, and rostral and caudal portions of the left middle frontal gyrus (cluster 1; p = .004), and left superior frontal gyrus (cluster 2; p = .004) was observed in HIV-infected patients with working memory deficit compared with those without such deficit. Negative correlations were found between WAIS-III–based Z scores and cortical thickness in the two clusters (cluster 1: ρ = –0.59; cluster 2: ρ = –0.47). Conclusion HIV-infected patients with working memory deficit have regions of greater thickness in the left frontal cortices compared with those without such deficit, which may reflect increased synaptic contacts and/or an inflammatory response related to the damage caused by HIV infection.

Exosomal miR-132-3p from Mesenchymal Stromal Cells Improve Synaptic Dysfunction and Cognitive Decline in Vascular Dementia

Background/Aims: Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Methods: Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24 h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR−132−3p), or miR-132-3p antago lentivirus (EXantagomiR−132−3p) intravenously. Behavioral and cognitive tests were performed and the mice were sacrificed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen-glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Results: Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR−132−3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR−132−3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR−132−3p treatment-induced functional improvement. In vitro, EXmiR−132−3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Conclusions: Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1.