My general interest encompasses many areas of neuroscience and molecular biology including cell
signaling mechanisms under normal as well as under stress conditions; the molecular mechanism of cognitive functions
and social behaviors, learning and memory; and the mechanisms of neurological diseases.
My specific interests include the role of oxidative stress and mitochondrial involvement in aging,
neurological or other disorders; moreover, the role of glial cells e.g. astrocytes in normal and pathological
functions of the nervous system.
There are tremendous amount of scientific information in the above mentioned areas, however, the obvious explanation is still missing.
Here are brief information about some disorders and the questions surrounding them. And if your curiosity has been aroused you are welcome
to visit the Knowledge Center with a click and find out more about the molecular mechanisms of cell functions and pathophysiology.
Stroke
Alzheimer's disease
Opioid addiction
Free radicals
Stroke
Stroke and cardiac arrest are major causes of death and disability, affect millions of individuals around the world and are
responsible for the leading health care costs of all diseases. A stroke occurs when blood vessels carrying oxygen and
other nutrients to a specific part of the brain suddenly burst (hemorrhagic stroke) or become blocked (occlusive or ischemic stroke). When blood fails to get through to
the affected parts of the brain, the oxygen supply is cut off, and brain cells begin to die. The injury results in
stroke syndromes including vertigo, sensory loss, nystagmus, anopia, facial numbness, ataxia, dysphagia, dysarthria,
ophtalamoplegia, hemiparesis, arm and leg paralysis, amnesia, color anomia, abulia, alexia, urinary incontinence or
coma depending on the arterial territory involved. An ischemic attack is often preceded by a transient ischemic
attack (TIA) with clinical symptoms typically lasting less than one hour. Several factors may play role in the
development of stroke such as environmental factors (e.g. smoking, alcohol consumption, oral contraceptives,
diet etc.), comorbidities (e.g. hypertension, coronary heart disease, atrial fibrillation, aneurysm, arteriovenous
malformation, atherosclerosis, diabetes mellitus etc.) and genetic factors (e.g. age, race etc.).
Although, intracellular events including the mitochondria-related apoptotic cell death pathway, mitochondrial
permeability transition, heat shock protein synthesis and free radical production of the brain cells (including
neurons and astrocytes) seems to play a major role in the molecular mechanism, the above mentioned risk facotrs
complicate the work to find the underlying mechanisms and find uniformed therapy for stroke patient. Morover,
there are only few human studies of brain biochemical changes after stroke, most studies regarding the pathophysiology
of cerebral ischemia have been done in experimental animal models including transgenic and
knock-out mice, as well as in in vitro models such as oxygen and glucose deprivated cell cultures or brain slices. This leads to
that unfortunate realization that the hundreds of agents having neuroprotective effect
in experimental models have failed in clinical trials.
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Alzheimer's disease
Alzheimer’s disease (AD) is characterized by cognitive deterioration affecting 5 million people in the USA.
The brain of Azheimer’s patients marked by extracellular amyloid-beta deposits and intracellular neurofibrillary
tangles. Amyloid-beta peptide (A-beta) may be at the root of neurodegeneration and the mechanism by which amyloid-beta
induces neurotoxicity appears to be mediated by oxidative stress.
The A-beta of different sizes, A-beta(1-40) and (1-42) results from the cleavage of the amyloid precursor protein (APP)
which is a ubiquitously expressed integral membrane protein that is cleaved in two distinct pathways. In the non-amyloidogenic
pathway, the cleavage of APP release a soluble APP-alpha which is thought to regulate neuronal excitability, plasticity, and survival.
In the amyloidogenic pathway, the cleavage of APP by beta-secretase, which is a membrane-bound aspartyl protease (BACE), generates a 99
amino acid C-terminal APP fragment, which is further cleaved by the gamma-secretase complex consists of several proteins including
presenilin 1 and 2. The resulting A-beta aggregate and form plaques which is a characteristic feature of Alzheimer’s brain.
In the familial cases, the mutation in either the APP gene or the presenilin 1 gene result in increased production of A-beta peptides.
Both A-beta peptides are toxic; however, the insoluble A-beta is more capable of aggregating into plaques. The mechanism by which A-beta
peptides induces neurotoxicity appears to be mediated by oxidative stress. A-beta peptides have been reported to produce hydrogen peroxide
by scavenging transition metals such as copper or iron, initiating a process resulting in the production of other ROS such as the highly
reactive hydroxyl radical which can attack DNA, proteins and fatty acids.
Although, genes have been implicated in AD, these cases only encircle 1% of all AD patient and the rest fall into category called sporadic meaning that
the mechanism of these cases are still elusive.
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Opioid addiction
Since long, research has been conducted in order to find and optimal painkiller which relieve selectively the pain
without any side effects or alterating psychologycal function of the brain.
Another urgent need is the discovery of the molecular mechanism of opioid tolerance and dependence.
Opioids can be defined as all the natural, synthetic, semi-synthetic morfin agonist, antagonist and morphomimetic peptides.
The term opiate marks only the morphomimetic derivatives of the opium (poppy) alkaloids that is morphin and codein semi-synthetic
derivatives (e.g. heroin). The analgetic ability of the opioid molecules depends on the presence of its receptors on the cell surfaces.
Many endogen opioid compounds produced by the organisms and act on wild scale of opioid receptor types (mu, delta, kappa) and subtypes
causing various effects.
These effects include the most important analgetic effect mediated mostly by mu receptors. The mechanism, these receptors alleviate pain
can be realized by spinal and supraspinal level with either incrising the threshold of the pain stimuli or modulate the emotional reactions.
These information based on the localization of opioid receptors in areas of the central nervous system which are parts of the monoaminerg
analgetic pathways (e.g. dorsal horn of the spinal cord, thalamus, amygdala, hippocampus, periaquaeductal area and brain stem nuclei - nucleus raphe magnus, nucleus paragigantocellularis).
Other physiological effects include euphoria=”well-being”, sedation, slowness of mental functions=“mental clouding”, breathing depression
(decreased sensitivity of the medullar breathing centrum to carbonic-dioxide), antitussive (depression of the medullar antitussive centrum),
emesis (area postrema), narrowed pupil (stimulation of nucleus oculomotorius/ Edinger-Westfal), catatony, cardiovascularis effects - hypotonia,
gastrointestinal effects- obstipatio (inhibition of acetil-kolin release), neuroendokrin effect –stimulation of prolaktin, adrenocorticotrop hormon,
somatotrop hormon release and inhibition of oxitocin, antidiuretic and lutheotropic hormon release.
Cronic usage of opioids leads to addiction such as tolerance and dependence. The mechanism of above mentioned phenomenons
are in the focus of research up to the present. The hypothesis include receptor desensitization (dissociation of receptor and G-protein),
internalization (cell surface receptors internalized by microsomes) and down-regulation (number of receptors decreases).
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Free radicals
Since the discoveries of free radicals in the living organisms investigation began to explore the role of free
radical species in the cellular mechanisms. Free radicals are highly reactive molecules causing oxidative stress and
damage cellular macromolecules (proteins, lipids and nucleic acids). They have been implicated in several pathophysiologic
conditions such as ischemic-reperfusion injury, cardiovascular disease, Alzheimer's Disease, cancer and aging.
Free radical production involves every organ of the body including the brain and are characterized as molecules involved in
neurotoxicity and neurodegeneration. However, recent evidence suggests that free radicals also function as small messenger molecules that
are normal components of signal transduction cascades during physiological processes such as long-term potentiation (LTP) in the hippocampus
involved in learning and memory.
Free radicals are generated by many different systems in the cell, however, the mitochondria is the major site of the free radical production.
Mitochondrial dysfunction and increased free radical production may lead to neuronal and astrocyte cell death resulting in altered brain functions.
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