ABSTRACT
In primary dissociated hippocampal cell cultures from 18-day-old mouse embryos, streptozotocin in concentrations of 2-5 mM produced a dose-dependent cytotoxic effect on day 3 in vitro, whereas on day 11 of culturing, the neurons were resistant to streptozotocin. The neurons in the 3-day cultures were functionally immature, which was seen from their weak spontaneous bioelectric activity in the form of rare single action potentials; by day 11 of culturing, the neurons reached a high level of differentiation and their functional properties acquired a character of network burst activity. Thus, streptozotocin had the most pronounced cytotoxic effect on immature hippocampal neurons in vitro.
Subject(s)
Antibiotics, Antineoplastic/toxicity , Neurons/drug effects , Streptozocin/toxicity , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cell Differentiation/drug effects , Dose-Response Relationship, Drug , Embryo, Mammalian , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/physiology , Mice , Mice, Inbred BALB C , Neurons/cytology , Neurons/physiology , Primary Cell Culture , Time FactorsABSTRACT
Focal unilateral traumatic brain injury in the sensorimotor cortical region disturbed the functions of contralateral limbs controlled by the damaged hemisphere. A single intravenous injection of methylene blue (1 mg/kg) immediately before or 30 min after the injury significantly weakened functional disorders in the affected extremities. In vitro experiments showed that methylene blue effectively reduced death of cultured neurons provoked by paraquat or zinc ions producing the toxic effects on mitochondrias.
Subject(s)
Brain Injuries, Traumatic/drug therapy , Methylene Blue/therapeutic use , Neuroprotective Agents/therapeutic use , Animals , Cells, Cultured , Male , Neurons/drug effects , Neurons/metabolism , Paraquat/therapeutic use , Rats, WistarABSTRACT
A cascade of pathological changes in the intact hemisphere developed in rats 6 months after focal unilateral traumatic brain injury: neuronal degeneration, hyperexpression of α-synuclein, APP (ß-amyloid peptide precursor) protein, and glutamine synthetase in cells other than astrocytes. The development of these changes in the contralateral hemisphere indicated the emergence of extensive delayed neurodegenerative processes in the brain after traumatic brain injury, which were characteristic of diseases associated with pathological aging.
Subject(s)
Brain Injuries, Traumatic/pathology , Cerebrum/pathology , Neurodegenerative Diseases/pathology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Astrocytes/metabolism , Astrocytes/pathology , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/genetics , Brain Injuries, Traumatic/physiopathology , Cerebrum/metabolism , Cerebrum/physiopathology , Delayed Diagnosis , Gene Expression , Glutamate-Ammonia Ligase/genetics , Glutamate-Ammonia Ligase/metabolism , Male , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/physiopathology , Rats , Rats, Wistar , Time Factors , Up-Regulation , alpha-Synuclein/genetics , alpha-Synuclein/metabolismABSTRACT
Addition into the culture medium of the antioxidant N-acetylcysteine (NAC, 1 mM) in the presence of Cu2+ (0.0005-0.001 mM) induced intensive death of cultured rat cerebellar granule neurons, which was significantly decreased by the zinc ion chelator TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine). However, the combined action of NAC and Zn2+ did not induce destruction of the neurons. Measurement of the relative intracellular concentration of Zn2+ with the fluorescent probe FluoZin-3 AM or of free radical production using a CellROX Green showed that incubation of the culture for 4 h with Cu2+ and NAC induced an intensive increase in the fluorescence of CellROX Green but not of FluoZin-3. Probably, the protective effect of TPEN in this case could be mediated by its ability to chelate Cu2+. Incubation of cultures in a balanced salt solution in the presence of 0.01 mM Cu2+ caused neuronal death already after 1 h if the NAC concentration in the solution was within 0.005-0.05 mM. NAC at higher concentrations (0.1-1 mM) together with 0.01 mM Cu2+ did not cause the death of neurons. These data imply that the antioxidant NAC can be potentially harmful to neurons even in the presence of nanomolar concentrations of variable valence metals.
Subject(s)
Acetylcysteine/toxicity , Apoptosis/drug effects , Copper/toxicity , Neurons/drug effects , Oxidative Stress/drug effects , Animals , Cells, Cultured , Cerebellum/cytology , Cerebellum/drug effects , Cerebellum/metabolism , Chelating Agents/pharmacology , Copper/chemistry , Ethylenediamines/pharmacology , Microscopy, Fluorescence , Neurons/cytology , Neurons/metabolism , Polycyclic Compounds/chemistry , Rats , Rats, Wistar , Zinc/pharmacologyABSTRACT
Alzheimer's disease is characterized by progressive memory loss and cognitive decline accompanied by degeneration of neuronal synapses, massive loss of neurons in the brain, eventually resulting in complete degradation of personality and death. Currently, the cause of the disease is not fully understood, but it is believed that the person's age is the major risk factor for development of Alzheimer's disease. People who have survived after cerebral stroke or traumatic brain injury have substantially increased risk of developing Alzheimer's disease. Social exclusion, low social activity, physical inactivity, poor mental performance, and low level of education are among risk factors for development of this neurodegenerative disease, which is consistent with the concept of phenoptosis (Skulachev, V. P., et al. (1999) Biochemistry (Moscow), 64, 1418-1426; Skulachev, M. V., and Skulachev, V. P. (2014) Biochemistry (Moscow), 79, 977-993) stating that rate of aging is related to psychological and social aspects in human behavior. Here we assumed that Alzheimer's disease might be considered as an exacerbation of senile phenoptosis. If so, then development of this disease could be slowed using mitochondria-targeted antioxidants due to the accumulated data demonstrating a link between mitochondrial dysfunction and oxidative stress both with normal aging and Alzheimer's disease.
