Kazimierz Gasiorowski

Flavones from Root of Scutellaria Baicalensis Georgi: Drugs of the Future in Neurodegeneration?

Flavonoids are natural, plant-derived compounds which exert diverse biological activities, also valuable neuroprotective actions within the brain and currently are intensively studied as agents able to modulate neuronal function and to prevent age-related neurodegeneration. Among them, flavones isolated from Scutellaria baicalensis root exhibit strong neuroprotective effects on the brain and are not toxic in the broad range of tested doses. Their neuroprotective potential has been shown in both oxidative stress-induced and amyloid-beta and alpha-synuclein-induced neuronal death models. Baicalein, the main flavone present in Scutellaria baicalensis root, strongly inhibited aggregation of neuronal amyloidogenic proteins in vitro and induces dissolution of amyloid deposits. It exerts strong antioxidative and anti-inflammatory activities and also exhibits anti-convulsive, anxiolytic, and mild sedative actions. Importantly, baicalein, and also another flavone: oroxylin A, markedly enhanced cognitive and mnestic functions in animal models of aging brains and neurodegeneration. In the preliminary study, wogonin, another flavone from Scutellaria baicalensis root, has been shown to stimulate brain tissue regeneration, inducing differentiation of neuronal precursor cells. This concise review provides the main examples of neuroprotective activities of the flavones and reveals their potential in prevention and therapyof neurodegenerative diseases.

Mitochondrion-Specific Antioxidants as Drug Treatments for Alzheimer Disease

Age-related dementias such as Alzheimer disease (AD) have been linked to vascular disorders like hypertension, diabetes and atherosclerosis. These risk factors cause ischemia, inflammation, oxidative damage and consequently reperfusion, which is largely due to reactive oxygen species (ROS) that are believed to induce mitochondrial damage. At higher concentrations, ROS can cause cell injury and death which occurs during the aging process, where oxidative stress is incremented due to an accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms. Neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, causing a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion whos DNA has been compromised. Therefore, mitochondria specific antioxidants such as acetyl-L-carnitine and R-alphalipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and amyloid beta oxidation and making these antioxidants very powerful alternate strategies for the treatment of AD.

Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer's disease: a new approach to therapy.

Vascular and metabolic dysfunctions and mitochondrial failure are now believed to be contributors to Alzheimer’s disease (AD) pathogenesis. Vascular dysfunction includes reduced cerebral blood flow (CBF), blood-brain barrier (BBB) disturbances and cerebral amyloid angiopathy (CAA). Mitochondrial failure results in deregulation of Ca 2+ homeostasis and elevated reactive oxygen species (ROS) generation, both of which are linked to neurotoxicity. Increased levels of ROS stimulate proinflammatory gene transcription and release of cytokines, such as IL-1, IL-6, and TNF-α, and chemokines, thereby inducing neuroinflammation. Conversely, inflammatory reactions activate microglia and astrocytes to generate large amounts of ROS, so neuroinflammation could be perceived as a cause and a consequence of chronic oxidative stress. The interaction between oxidative stress and neuroinflammation leads to amyloid-β (Aβ) generation. The deposition of Aβ peptide in the brain generates a cascade of pathological events, including the formation of neurofibrillary tangles (NFTs), inflammatory reactions, increased oxidative stress and mitochondrial dysfunction, which are causative factors of cell death and dementia. The purpose of this paper is to provide current evidence on vascular dysfunction and mitochondrial failure, both in neurons and glia and in brain vascular wall cells in the context of potential application for treatment of AD and other neurodegenerations.

Implication of Oncogenic Signaling Pathways as a Treatment Strategy for Neurodegenerative Disorders – Contemporary Approaches

Recent evidence has associated the aberrant, proximal re-expression of various cell cycle control elements with neuronal cell vulnerability in Alzheimers and Parkinsons diseases, as a common chronic neurodegeneration. This phenomenon associated with oncogenic transduction pathway activation has attracted the interest of scientists all over the world for a few years now. The purpose of this paper is to outline areas of research related to oncogenic factors or medicines in the context of potential applications for future treatment of the above mentioned chronic and, largely, incurable diseases.

Nanotechnology for Alzheimer Disease

BACKGROUND Alzheimer disease (AD) typically affects behavior, memory and thinking. The change in brain have been reported to begin approx. 10-20 years before the appearance of actual symptoms and diagnosis of AD. An early stage diagnosis and treatment of this lethal disease is the prime challenge, which is mainly halted by the lack of validated biomarkers. METHOD Recent nanotechnological advancements have the potential to offer large scale effective diagnostic and therapeutic options. Targeted drug (e.g. Rivastigmine) delivery with the help of nanoparticles (NPs) in the range of 1-100 nm diameters can effectively cross the blood brain barrier with minimized side effects. Moreover, biocompatible nanomaterials with increased magnetic and optical properties can act as excellent alternative agents for an early diagnosis. With the high volume of research coming in support of the effective usage of NP based drug delivery in critical environment of CNS, it is quite likely that this approach can end up providing remarkable breakthroughs in early stage diagnosis and therapy of AD. CONCLUSION In the current review, we have presented a comprehensive outlook on the current challenges in diagnosis and therapy of AD, with an emphasis on the effective options provided by biocompatible NPs as imaging contrast agents and drug carriers.

Insulin Resistance in Alzheimer Disease: p53 and MicroRNAs as Important Players

Glucose homeostasis is crucial for neuronal survival, synaptic plasticity, and is indispensable for learning and memory. Reduced sensitivity of cells to insulin and impaired insulin signaling in brain neurons participate in the pathogenesis of Alzheimer disease (AD). The tumor suppressor protein p53 coordinates with multiple cellular pathways in response to DNA damage and cellular stresses. However, prolonged stress conditions unveil deleterious effects of p53-evoked insulin resistance in neurons; enhancement of transcription of pro-oxidant factors, accumulation of toxic metabolites (e.g. ceramide and products of advanced glycation) and ROS-modified cellular components, together with the activation of proapoptotic genes, could finally induce a suicide death program of autophagy/apoptosis in neurons. Recent studies reveal the impact of p53 on expression and processing of several microRNAs (miRs) under DNA damage-inducing conditions. Additionally, the role of miRs in promotion of insulin resistance and type 2 diabetes mellitus has been well documented. Detailed recognition of the role of p53/miRs crosstalk in driving insulin resistance in AD brains could improve the disease diagnostics and aid future therapy.

Vascular factors and epigenetics modifications in the pathogenesis of Alzheimer?s disease

A disease (AD) is an age-associated, irreversible, progressive neurodegenerative disease that is characterized by severe memory loss, unusual behavior, personality changes, and a decline in cognitive function. The drugs currently available to treat the disease have limited effectiveness. It is believed that therapeutic intervention that could postpone the onset or progression of Alzheimer’s disease would dramatically reduce the number of cases in the coming years. This study demonstrates the protective effect of acteoside enriched fraction from the leaves of Colebrookia oppositifolia on Intracerebroventricular-streptozotocin (ICV-STZ) induced Alzheimer’s in rats. Chronic treatment with AEF (5, 10 and 20 mg/ kg) on a daily basis for a period of 21 days, beginning 1 h prior to first ICV-STZ injection, significantly improved cognitive impairment. Oxidative stress and neuroinflammation have been implicated in pathophysiology of sporadic type of dementia. Besides, improving cognitive dysfunction, administration of AEF significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione reductase levels in brain tissues. The ICV STZ injection showed a significant decline in the brain acetylcholine levels. However, administration of ASF (5, 10 and 20 mg/kg) significantly reversed the elevation in acetylcholine esterase activity STZ induced Alzheimers altered peripheral T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental animals. Oral administration of AEF decreased the over expressed cell population of CD4+ and CD8+ T cell evident by significant decrease in expression of IFN-γ. This preclinical study establishes the unique potential of AEF suggesting its use in AD. Such plant products are sort after to carry out the treatment and prevent the cognitive impairment. There is an urgent need for the implementation of combined and coordinated research endeavors for the development of such herbal moieties for therapeutic interventions and prevention of AD, thus, improving the quality of life of the patients.O current understanding of the pathogenic mechanism of Alzheimer’s disease (AD) is based mainly on rare variants with large effect size, however the identification of such variants remains elusive. To identify novel genes and variants with large effect size, we performed exome-sequencing in 14 families with late-onset AD, identifying and following-up all the variants that showed perfect segregation. A rare variant in PLD3 (rs145999145; V232M) segregated with disease status in two independent families, and showed large effect size for AD risk (OR=3.48; p=8.9×10-8). This variant was present in 0.8% of the sequenced samples in the EVS and 0.43% of healthy elderly population (4/922). We have also followed up all the genes that segregated with disease status in 400 AD cases and 1080 controls. A total of 60 genes (DFNB31, NFATC1, LRP4, CACNA1G, CALCR, ZNF30, DMRT2, KIF1A, ZNF341, LRP4, PRKD2) were selected. As replication, the most interesting genes were resequenced in additional 800 cases and 400 controls. In order to analyze the association of the selected genes in disease risk we performed gene-based test stratifying by minor allele frequency (MAF), and by analyzing variants that were unique to cases or controls. One gene showed a significant gene-based association (variants MAF<1%) with AD risk after multiple testing (OR=1.97, p=2.51x10-4). The analyses indicated that additional genes harboring low-frequencies risk variants exist, and that, family-based studies could help identify such genes and variants. We are currently performing additional sequencing and functional analyses to validate our findings.T amyloid precursor protein (APP) is a broadly expressed transmembrane protein that plays a significant role in the pathogenesis of Alzheimer’s disease (AD). APP can be cleaved at multiple sites to generate a series of fragments including the amyloid β (Aβ) peptides and APP intracellular domain (AICD). While Aβ peptides have been proposed to be the main cause of AD pathogenesis, the role of AICD has been underappreciated. Here we report that APP induces AICD-dependent cell death in Drosophila neuronal and non-neuronal tissues. Our genetic screen identified the transcription factor FoxO as a crucial downstream mediator of APP-induced cell death and locomotion defect. In mammalian cells, AICD physically interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus upon oxidative stress, and promotes FoxOinduced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death and locomotion defect through AICD, which acts as a transcriptional co-activator of FoxO.Our studysheds light on the potential therapeutic target of Alzheimer’s disease.Background:One of the debilitating signs of Alzheimer’s disease is the loss of memory. Then, there has been always an interest to know the neurotransmitters, which mediate memory in order to assess their involvement in such neurodegenerative disorders. Opioid receptors are a group of G protein-coupled receptors, which arewidely distributed in the brain andmemory-related structures such as hippocampus. In 1799, Friedrich Serturner discovered the major active ingredient of opium, which he named morphine and today is used as a pharmacological tool to assess opioid receptors role. Memory is considered to have different phases: acquisition, consolidation and retrieval. Hippocampus is the major structure involving in learning and memory. Morris water maze is a golden test assessing spatial memory which is a hippocampal function. As the opioid receptors exist in the hippocampus there was always an interest to assess the effect of opioids on learning and memory. Most of the research, however; has focused on chronic opioids usage than acute usage of them; therefore the effect of acute administration of morphine on memory consolidation in Morris water maze has not been elucidated yet. This research was aimed to assess the role of morphine on water maze memory consolidation.Methods: Adult male Sprague-Dawely rats weighing 230-270 g were trained in a single session consisting of 8 trials. The probe test was done 24 hours later to assess memory retention. To assess the effect of morphine (10mg/kg/SQ) on consolidation phase, it was injected immediately after training. In another group naloxone was used to examine if the effect was exerted by morphine was directly related to opioid receptors. Results: The results showed that post-training administration of morphine deteriorates learning as the trained rats spent less percentage of time in target zone at probe trial. In addition, co-administration of naloxone and morphine prevented morphine effect on memory consolidation showing that morphine induces memory consolidation defect via opioid receptors. Conclusions: This study might indicate that acute over activation of opioid receptors disruptsmemory consolidation processes, which helps us in knowing more about neurotransmitters and their role in learning and memory.