Subsequent to an hypoxic-ischaemic (HI)-insult a multi-faceted complex cascade of events occurs that ultimately results in cellular and neurological impairments within cortical and sub-cortical central nervous system (CNS) regions. In the present studies a modified �Levine� rat-pup model of HI (left carotid artery ligation + 1 hour global hypoxia on post-natal day (PND) 26) was employed to assess the neuroprotective properties of clomethiazole (CMZ; a γ-aminobutyric acid (GABA)A receptor agonist). In this study, histological and electrophysiological paradigms were used to assess the long-term neuroprotective properties of CMZ (414mg/kg/day via mini-pumps). Key enzymes involved in inflammation, namely nitric oxide synthase (NOS) and arginase, were also examined to assess other potential CMZ mechanisms. Assessments were carried out 3- and 90-days post-HI, with extensive ipsilateral CNS lesions evident at a gross histological level, at both the early and long-term stages, with CMZ significantly decreasing the lesion size at 3- and 90-days (P<0.01; P<0.05). Evoked field potential analyses were used to assess hippocampal CA1 neuronal activity ex vivo. Electrophysiological measurements contralateral to the occlusion revealed impaired neuronal function following HI relative to short- and long-term controls (P<0.001, 3- and 14-days; P<0.01, 90-days), with CMZ providing near complete protection (P<0.001 at 3- and 14-days; P<0.01 at 90-days). Both inducible NOS (iNOS) and arginase activities were significantly increased at 3-days (P<0.01), with arginase activity remaining elevated at 90-days post-HI (P<0.05) ipsilaterally. CMZ suppressed the HI-induced increase in iNOS and arginase activities (P<0.001; P<0.05). These data provide evidence of long-term functional neuroprotection afforded by CMZ in a model of HI-induced neurodegeneration. In addition, under conditions of HI, functional deficits were not restricted to the ipsilateral hemisphere and were due, at least in part, to changes in the activity of NOS and arginase. Underlying mitochondrial dysfunction is eminently present in many neuropathological conditions. The full extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues was assessed following HI. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-days post-HI revealed a significant decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, significant changes in respiratory function were also evident in contralateral regions and cerebellum, 3-days post-HI (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I-V) and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed ipsilateral mitochondrial impairment following HI. Complexes I, II-III, V and citrate synthase were also impaired, in contralateral regions and cerebellum, 3-days post-HI. CMZ treatment provided significant protection to all mitochondrial aspects of neuronal tissue assessed. This study provides evidence of the full extent of mitochondrial damage following an HI-insult and may contribute, in part, to the impairment seen contralaterally. In addition, protection afforded by CMZ extends to preservation of mitochondrial function and integrity. Cerebral ischaemia-induced angiogenesis has been shown within and around infarcted regions and may contribute to a more favourable neurological outcome. The level of angiogenesis was examined using platelet endothelial cell adhesion molecule-1 (PECAM-1 / CD31). CD31 immunolabelling 7-days post-HI revealed a significant increase in angiogenesis compared with non-intervention controls (P<0.001). Treatment with CMZ decreased the level of angiogenesis compared to HI + saline (P<0.001) back to non-intervention control levels. Conversely, N[omega]-nitro-L-arginine methyl ester (L-NAME) treatment (5mg/kg/day) exacerbated the ischaemic lesion (P<0.001) and resulted in a marked decrease in angiogenesis compared to non-intervention controls (P<0.001). The extent of cerebral infarction in these studies is dependent on the level of NOS activity with CMZ increasing total NOS levels compared to HI + saline, while L-NAME halted the HI-induce increase in total NOS activity (P<0.001). These results show for the first time, that angiogenesis may be used as an assessment of neurodegeneration / neuroprotection in pathologies of cerebral ischaemia and are directly correlated with changes in NOS activity. These studies have therefore shown that following HI, damage also occurs contralateral to the occlusion, and is not restricted to the ipsilateral hemisphere. In addition, the neuroprotective effects of CMZ have been shown to extend out to 90-days post-HI, whereby significant protection to CA1 neuronal activity was seen. These studies also provide in vivo evidence that CMZ may also afford neuroprotection via anti-inflammatory pathways, as evidenced by a decrease in iNOS and arginase activities. Furthermore, these studies have also show evidence that angiogenesis (CD31) can be used as a diagnostic tool to assess neuroprotection / neurodegeneration.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [121]-138).

Philosophiae Doctor - PhD / The family Amaryllidaceae is widely distributed in the southern hemisphere. Members of the family are well known for their content of pharmacologically active alkaloids and represent an important epicentre of Amaryllidaceae-alkaloid diversity. Other metabolites from Amaryllidaceae, such as phenolics including flavonoids, lignans, chromones, and acetophenones, in addition to terpenoids and ceramides have been reported. Boophone haemanthoides (BHE), Crossyne flava (CRO), Clivia miniata (CME) and Nerine humilis (NHE) are members of Amaryllidaceae that have shown biological activity. Parkinson’s disease (PD) is a neurodegenerative disease that progresses with increasing age and some of its major symptoms include tremors, postural and movement related difficulties. To date, the treatment of PD remains a challenge because available drugs only treat the symptoms of the disease or possess serious side effects. In light of this, new treatment options are needed, hence this study investigates the neuroprotective effects of BHE and CRO along with the isolated compounds of BHE and CRO. / 2022

Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by cell death in the substantia nigra pars compacta (SNpc) and the appearance of aggregated α-synuclein (α-syn). Autophagosomes accumulation and lysosomal reduction were discovered in PD patients' brain, which indicated the deficiency of autophagy in the progress of PD. TFEB (transcription factor EB) is a member of basic helix -loop-helix-leucine-zipper transcription factors (MiT family) and is a key master monitor for autophagy and lysosome biogenesis. Overexpression of TFEB is able to rescue the dopaminergic neurons (DAs) loss and α-syn aggregated in α-syn transgenic mice model and MPTP PD model. Hence, in recent years, many researchers have considered TFEB as a new therapeutic target for PD In this study, we discovered a novel TFEB activator named E4 by screening synthesized curcumin analogs. We have found that E4 strongly promoted TFEB nuclear translocation and induced autophagy in different cell lines. TFEB is essential for E4-induced autophagy flux. We also demonstrated that the underlying mechanism of E4 activate TFEB is mainly through inhibiting mTORC1 activity. We constitutively activate mTOR by knockdown TSC2 abrogated the increase of LC3-II and decrease of p-TFEB. We further estimated the protective effects of E4 in overexpressed α-syn model and neurotoxins induced cytotoxicity model. Treated with E4 for 48h in N2a transfected with A53T α-synuclein cells dose-dependently reduce the α-synuclein level. At the same time, we established the MPP+ model in PC12 cells which is pre-treated cell with E4 for 6 hours and then co-treated cells with MPP+ for 48 hours. The cell viability results showed that E4 significantly protect PC12 cells against MPP+ cytotoxicity dose-dependently. E4 had shown good neuroprotective effects in PD in vitro models while poor water solubility and low brain permeability restricted its application in PD animal models. Hence, assembling E4 molecules into self-carried nanoparticles (NanoE4) addressed the issue of poor water solubility and intranasal administration solved the problem of low permeability. In order to track NanoE4 release in vitro and in vivo, we further investigated the absorption and emission of NanoE4. However, the absorption fluorescence results showed that NanoE4 exhibits the strong aggregation-caused quenching effect (ACQ) due to π-π stacking of the planar molecule within the NPs. NanoE4 have much weak emission compared with E4 molecules. Therefore, we fabricated E4-TPAAQ NPs by co-reprecipitating E4 molecules with the reported fluorescent organic compound TPAAQ (2,6-Bis[4-(diphenylamino) phenyl] anthraquinone). Next, we developed an intranasal drug delivery system in our lab. After intranasal co-drop nanodrug E4-TPAAQ NPs for 24 hours, we observed strong fluorescence distributed in the brain which indicated that deliver nanoparticles into the brain successfully through nasal-brain system. Therefore, we examined the protective effect of NanoE4 in MPTP-induced PD mice model. In MPTP models, we found autophagy dysfunction, motor function decrease and increase of α-synuclein as reported previously. Treatment with NanoE4 rescued the motor dysfunction induced by MPTP. NanoE4 also increase TH level in the striatum part of midbrain. NanoE4 treatment also decreased the α-synuclein protein aggregate in both SNpc and striatum. Overall, these results demonstrate the neuroprotection NanoE4 against PD. Collectively, our findings 1) discovered a novel TFEB activator E4 that inhibited the mTOR pathway 2) indicated in vitro and in vivo experimental evidence for TFEB activator as the anti-PD drug candidate 3) provide a novel drug develop and delivery system for potential PD that limited by water solubility and BBB (blood-brain barrier) obstacle

In February 2012, the FDA issued safety label changes and monitoring requirements for statin therapy. A risk of cognitive impairment was noted, although evidence was largely based on observational data, including case reports. In 2014, the National Lipid Association's safety task force found that evidence does not support cognitive decline as a classwide effect for statins. Some evidence has shown that statins may actually have beneficial effects on cognition. This article discusses management of statin therapy in patients with cardiovascular risk who may experience cognitive decline or have cognitive impairment, such as Alzheimer disease.

No description available.

Xian, Jiawen. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 201-230). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

A hidrocefalia é uma doença que afeta não só a dinâmica do líquido cefalorraquidiano, mas também outras estruturas do sistema nervoso central. Apesar do tratamento com derivações liquóricas ser eficiente na redução da ventriculomegalia, muitos danos neurológicos não são revertidos com a cirurgia. Vários estudos demonstram que o estresse oxidativo está envolvido na gênese das lesões na hidrocefalia. Objetiva-se avaliar os efeitos da quercetina nas lesões secundárias à hidrocefalia experimental em ratos. Foram utilizados ratos machos com sete dias de vida, que recebem a injeção de caulim a 15% na cisterna magna para indução da hidrocefalia. Foram divididos em grupo controle (C), hidrocefálico não tratado (HN), hidrocefálico derivado (HD), hidrocefálico tratado com água destilada (HA), hidrocefálico tratado com água destilada e derivação (HDA), hidrocefálico tratado com quercetina peritoenal (HQp), hidrocefálico tratado com quercetina peritoneal e derivação (HDQp), hidrocefálico tratado com quercetina por gavagem (HQg), hidrocefalcio tratado com quercetina por gavagem e derivação (HDQg). A quercetina apresentou significativamente uma melhora nos marcadores imunoistoquimicos, principalmente caspase-3 e GFAP. Não houve alteração significativa na avaliação clinica/comportamental. A utilização da quercetina isolada não altera o volume e tamanho ventricular e a realização de derivação ventriculo-subcutânea em ratos recém-nascidos com hidrocefalia apresenta uma alta morbi-mortalidade / Hydrocephalus is a disease that affects not only the dynamics of the cerebrospinal fluid, but also other structures of the central nervous system. Although CSF derivation is effective in reducing ventriculomegaly, many neurological damage is not reversed with surgery. Several studies have shown that oxidative stress is involved in the genesis of hydrocephalus lesions. The objective of this study was to evaluate the neuroprotective response of quercetin in hydrocephalus. Male rats with seven days of life were used, which received the 15% kaolin injection in the cisterna magna for induction of hydrocephalus. They were divided into control group (C), untreated hydrocephalic (HN), derived hydrocephalic (HD), hydrocephalic treated with distilled water (HA), hydrocephalic treated with distilled water and shunt (HDA), hydrocephalic treated with quercetin peritoenal (HQp), hydrocephalic treated with quercetin peritoneal and derivation (HDQp), hydrocephalic treated with quercetin by gavage (HQg), hydrocephalus treated with quercetin by gavage and bypass (HDQg). Quercetin significantly improved the immunohistochemical markers, mainly caspase-3 and GFAP. There was no significant change in clinical / behavioral assessment. The use of isolated quercetin does not alter the volume and ventricular size and the realization of ventriculo-subcutaneous shunt in newborn rats with hydrocephalus presents a high morbi-mortality

Oxidative stress causes neural damage and inhibits essential cellular processes, such as synaptic transmission. Despite this knowledge, currently available pharmaceutical agents cannot effectively protect neural cells from acute oxidative stress elicited by strokes, heart attacks, and traumatic brain injuries in a real life clinical setting. Our lab has developed an electrophysiology protocol to identify novel drugs that protect an essential cellular process (neurotransmission) from acute oxidative stress-induced damage. Through this doctoral dissertation, we have identified three new drugs, including a Big K+ (BK) K+ channel blocker (iberiotoxin), resveratrol, and a custom made resveratrol-like compound (fly2) that protect synaptic function from oxidative stress-induced insults. Further developing these drugs as neuroprotective agents may prove transformative in protecting the human brain from acute oxidative stress elicited by strokes, heart attacks, and traumatic brain injuries. Inhibiting the protein kinase G (PKG) pathway protects neurotransmission from acute oxidative stress. This dissertation has expanded upon these findings by determining that the PKG pathway and BK K+ channels function through independent biochemical pathways to protect neurotransmission from acute oxidative stress. Taken together, this dissertation has identified two classes of compounds that protect neurotransmission from acute oxidative stress, including resveratrol-like compounds (resveratrol, fly2) and a BK K+ channel inhibitor (iberiotoxin). Further developing these drugs in clinical trials may finally lead to the development of an effective neuroprotective agent. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Cone snails are carnivorous marine mollusks, utilizing their neuropeptide-rich venom for prey capture. The venom of Conus brunneus, a wide-spread Eastern Pacific vermivore, has not been extensively studied. In the current work, peptides from the dissected venom were characterized and tested using preliminary bioassays. Six peptides (A-F) were isolated and tested. Three peptide identities were determined by comparison with previously reported data: bru9a (A), bru3a (F), and an a-conotoxin (E). Preliminary screening in a stroke-related model of induced glutamate excitotoxicity in primary neuronal cells and PC12 cell cultures indicated potential neuroprotective activity of peptide fractions A, D, and F. Further testing is necessary to determine and verify structure, activity, target, and mechanism of action of the promising peptides from C. brunneus, which may prove effective neuropharmacological agents to treat stroke. / by Rebecca A. Crouch. / Thesis (M.S.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.