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Natalia V Koudinova

Publications and source records attributed to Natalia V Koudinova.

6 recordsLinked to original sources
PubMed2004

Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.

We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD.

Alzheimer Disease↗
PubMed2003

Photodynamic therapy with Pd-Bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts.

Small cell carcinoma of the prostate (SCCP), although relatively rare, is the most aggressive variant of prostate cancer, currently with no successful treatment. It was therefore tempting to evaluate the response of this violent malignancy and its bone lesions to Pd-Bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT), already proven by us to efficiently eradicate other aggressive non-epithelial solid tumors. TOOKAD is a novel bacteriochlorophyll-derived, second-generation photosensitizer recently, developed by us for the treatment of bulky tumors. This photosensitizer is endowed with strong light absorbance (epsilon(0) approximately 10(5) mol(-1) cm(-1)) in the near infrared region (lambda=763nm), allowing deep tissue penetration. The TOOKAD-PDT protocol targets the tumor vasculature leading to inflammation, hypoxia, necrosis and tumor eradication. The sensitizer clears rapidly from the circulation within a few hours and does not accumulate in tissues, which is compatible with the treatment of localized tumor and isolated metastases. Briefly, male CD1-nude mice were grafted with the human SCCP (WISH-PC2) in 3 relevant anatomic locations: subcutaneous (representing tumor mass), intraosseous (representing bone metastases) and orthotopically within the murine prostate microenvironment. The PDT protocol consisted of i.v. administration of TOOKAD (4 mg/kg), followed by immediate illumination (650-800 nm) from a xenon light source or a diode laser emitting at 770 nm. Controls included untreated animals or animals treated with light or TOOKAD alone. Tumor volume, human plasma chromogranin A levels, animal well being and survival were used as end points. In addition, histopathology and immunohistochemistry were used to define the tumor response. Subcutaneous tumors exhibited complete healing within 28-40 days, reaching an overall long-term cure rate of 69%, followed for 90 days after PDT. Intratibial WISH-PC2 lesions responded with complete tumor elimination in 50% of the treated mice at 70-90 days after PDT as documented histologically. The response of the orthotopic model was also analyzed histologically with similar results. The study with this model suggests that TOOKAD-based PDT can reach large tumors and is a feasible, efficient and well-tolerated approach for minimally invasive treatment of local and disseminated SCCP.

Animals↗
PubMed2003

Cholesterol, synaptic function and Alzheimer's disease.

We experimentally modeled neuronal cholesterol imbalance by creating an acute biochemical increase in cholesterol turnover in rat hippocampal slices. This kind of experimental set-up impairs the redistribution of cholesterol from one cell to another via lipoprotein transport. While increasing cholesterol removal or immediately afterwards, we evoked and recorded two brain waveforms, paired pulse facilitation (PPF) and long-term potentiation (LTP), which indicate neurotransmission and synaptic plasticity, respectively. We found that the lack of cholesterol supply to neurons impaired both PPF and LTP. From additional immunofluorescent analysis of the slices, we could demonstrate that the cholesterol imbalance also caused neurodegeneration of hippocampal neural cell processes and the appearance of tau protein pathology in the mossy fibers. We also analyzed rats fed a cholesterol diet and discovered that they had increased hippocampal cholesterol biosynthesis and impaired LTP. Cholesterol-fed rats were also characterized by Alzheimer's-like brain amyloid that we did not observe in the model of acute cholesterol imbalance. Our data and research by others suggest that biological cholesterol homeostasis dysregulation itself plays a key role in synaptic plasticity impairment and neuronal degeneration, and is the primary cause for several Alzheimer's disease hallmarks not limited to brain amyloids. Moreover, changes in the neurochemistry of amyloid beta, tau, neuronal cytoskeleton, and oxidative stress reactions due to Alzheimer's likely represent physiological transitory mechanisms that aim to compensate impaired brain cholesterol dynamics and/or associated neurotransmission and synaptic plasticity failure. Part of this article was published as netprint and is available under the URL http://clinmed.netprints.org/cgi/content/full/2001100005v1.

Acetates↗