Cells can die via two manners, necrosis (death from injury incompatible with life) or apoptosis (programmed cell death or cellular suicide). Necrosis and apoptosis occur by a mechanism that has been at least partially conserved through animal evolution [1176]. The superficial difference between these two forms of death, swelling during necrosis and shrinking during apoptosis, is based on a difference in ionic processes. Necrosis is a pathological form of cell death caused by the direct result of external insults such as physical injury, energy depletion, toxic insults, acidic or osmotic damage, hypoxia and ischemia, leading to cell swelling and lysis with release of intracellular material and with the disruption of external and internal membranes [1176, 1198]. Apoptosis, in contrast, is an inborn cellular program of cell death associated with activation of a genetic plan [83, 351, 390, 1389, 942, 1198]. Apoptosis is often connected with the development and reorganization of brain, when a cell has two fortunes: to die or proliferate. The default apoptotic pathway is shutdown when development is complete, and growth factors are no longer required to prevent death, but most animal cells in adults retain the ability to activate their suicide program when they have lost their function during natural development or because of serious injury. During apoptosis, the nucleus and the cytoplasm are condensed and fragmented, and the cell shrinks. A curable necrotic damage that does not lead to death also revives developmental mechanisms that are connected with growth but not with proliferation. Apoptotic cells die being sufficiently healthy for their utilization during phagocytosis by macrophages or neighboring glial cells. Cells that have undergone necrosis usually are not phagocyted by macrophages.
Local injurious influences that are incompatible with life can, in the same tissue, evoke both necrosis and apoptosis. The ischemic center is characterized by cell necrosis, while apoptotic cells are located in the zone around the ischemic focus, the ischemic penumbra [532]. Hypoxia [1054] and ischemia [1318, 748] induce necrotic and apoptotic cell damage in a close relationship between them. After ischemia, neurons are the main cell type that dies [260], because of their high sensitivity to energetic metabolism. There are procedures that ameliorate cell damage and prevent cell death and these protective procedures reduce both necrotic and apoptotic cell death [59].
The healthy cell responds to impairment by a defensive homeostatic reaction and its reaction displays necrotic syndromes. If deviation from the norm is recoverable, the cell recuperates and remains intact, but if the severity of damage exceeds the possibilities of homeostatic compensation, the cell dies through necrosis. The necrotic cell dies in a struggle, the apoptotic cell passes away without struggle and, moreover, undertakes efforts in order to die when its environment is hopelessly altered, such as when a cell is deprived of growth hormone during individual development [227]. A short and strong impact usually evokes necrosis, while relatively small and protracted influences cause apoptosis. For example, calcium ionophores (which increase permeation for Ca?+) can induce either apoptosis or necrosis in cultured cortical neurons, dependent on ionophore concentration: a large concentration produces necrosis, a small and prolonged concentration provokes apoptosis [507]. Similarly, the length of time a neuron spends in a depolarized state following hypoxic depolarization is a critical determinant of the extent of reversible necrotic damage or irreversible apoptotic cell death [233]. Increased duration of acidosis to 60 minutes induced irreversible damage and neuronal loss in the hippocampus, while 30 minutes damage exerts reversible necrotic alterations [1366]. Tissue injury is related to the total duration and intensity of tissue depolarization and not to the frequency of depolarization [1027].
Strength and stretch of harm determine further the route of damage, but the quickness of each of the routes to death is also different. Necrotic and apoptotic deaths proceed in different time scales. Glutamate can induce either early necrosis or delayed apoptosis in cerebellum granule cells [41]. Apoptosis is a slow form of cell death, lasting for many hours or days, [83, 351, 390, 942]. In contrast, necrosis is a form of cell death that occurs rapidly (minutes or tens of minutes) in response to severe insult [546]. For instance, development of necrotic symptoms, such as a rapid loss of spine and dendrite structure [1426], change in spontaneous action potentials (APs) [836] and intracellular Na+ increase [416], is observed during the first few minutes after severe is-chemic damage, anoxia or mechanical injury. Within two minutes, protective mechanisms are activated, create an elevation in intracellular Ca?+, develop of Ca2+ wave and quickly returns Ca2+ to background levels [642]. Protective events within a neuron can prolong necrosis for several hours or days. For instance, approximately 24 h after axotomy, sensory neurons of Aplysia display neuritic outgrowth, enhanced cyclic AMP level and augmented excitability [1195].
A necrotic cell tries to survive by means of activation of recoverable home-ostasis, but an apoptotic cell reverses its resources into destruction and does not turn on homeostatic mechanisms. Many molecular, biochemical and genetic events occur within cells undergoing apoptosis. Some of these events are incompatible with cell survival because they have irreversible, catastrophic consequences. The onset of such changes marks the point of no return, an event termed ‘the commitment-to-die’ [227]. The way to the point of no return may be dependent on cell line and initial conditions, but the execution phase of apoptosis is evolutionary conserved and occurs with amazing temporal and morphological uniformity in most if not all cell types regardless of the circumstance and impacts used to induce death. Once this phase of apoptosis begins, death is inevitable [843]. Apoptosis proceeds with central control and cell dies conventionally after receiving of the signal to die and passing over the point of no return. After passing over this point, homeostasis does not work for cell recovery and this, evidently, is not associated with the exhausting of compensatory capabilities. Although harmful influences are slowly accumulated before a cell reaches the point of no return, there is a special signal to die and this signal may be outer or inner. A cell, for example may receive the inflammatory factor interleukin 1 (a member of the signaling family for the induction of apoptosis), or when cells lose unmanageable amounts of intracel-lular K +, cells have to initiate and execute the K+-sensitive suicide cascade [1386].
Oppositely, a cell may be subjected to necrotic damage only partially, depending on environment, on localization of damage, on impairment of the specific metabolic path and in accordance with experience. Protection at the early stage of necrosis also may be specific (see further) and lead the cell into an unusual stable state. During early development, the necrotic process is reversible [532]. For instance, alterations evoked by ischemia [1426], hypoxia [836, 233] and acidic stress [1366] may be recovered after cessation of injuring factor. Besides, there are many treatments that not only prevent development of necrotic damage (apoptosis also is possible to prevent), but treatments that reverse necrosis that already has begun.
If neuronal damage and death participate in an on-line control of animal cerebral activity, the mechanism can only be necrotic, which is relatively rapid, reversible in its early stages and may be specific in respect to prehistory. Further, we will pay attention, before all, to necrotic damage, but relative to apoptosis, we have to make one important remark. The commitment-to-die is the important point, connected with the switching off homeostasis. If a cell’s aspiration to live lies in the basis of the beginnings of psychics, then a solution of this paramount brain mystery is very important to understand: how does this distinctive property of the living cell disappear when a cell passes through the point of no return? At present, this problem remains a subject of considerable debate and controversy and details of this phenomenon are still necessary to determine. Nevertheless, even the existence of a point of no return is important: its existence means that a state of aspiration to life is a qualitatively special state. A given cell may or may not possess an aspiration to life, but it is impossible to live or to feel half-alive.
Necrotic damage is an extremely complex phenomenon. To be more accurate, the homeostatic compensation of necrotic damage is the most complex. Different forms of compensation are categorized by the means, times, pathways of recovery and even by a final point, which, generally speaking, does not coincide with the initial state. Compensation recovers the life of a cell and, therefore, is almost as complex as a life itself. We will describe only those attribute of damage that may concern mechanisms of brain behavior.
Neuronal damage and death have been extensively investigated [343, 797, 921, 1188, 796]. Mediators of the processes related to neuronal damage are excitatory amino acids (glutamate, NMDA, kainite, AMPA, etc.) retrograde transmitters (arachidonic acid, NO), neuropeptides and neurohormones, cy-tokines (interleukin 1, 6, 8, neurotensin, thyrotropin-releasing hormone etc.) and corticotrophin-releasing factor and these mediators are interdependent. For example, NMDA receptor activity leads to enhancement of intracellular Ca2+, release of nitric oxide (NO) and increases the formation of toxic hy-droxyl radicals.
Swelling of cells begins from Na+ influx through a hole in the cellular membrane after physical damage or through potential-dependent channels and glutamate-gated channels, because of physiological activity. Nevertheless, Na+ influx is not the primary reason of necrosis or the single reason of damage. The increase in intracellular Ca2+ is an important reason for neuronal injury, and damage is suppressed by inhibition of endogenous Ca2+. The rise in intracellular calcium may result also in the activation of Ca2+-dependent proteins and further increase the rate of membrane depolarization that leads to uncontrolled cellular swelling and necrosis [158]. A large intracellular concentration of Ca2+ in natural conditions usually follows excitation. Glutamate receptors (AMPA, NMDA, kainate and metabotropic receptors) are the main channels for transmission of excitation in the central nervous system and this excitation sometimes is excessive. Detrimental action of glutamate is, in particular, connected with a high permeability of different types of glutamate receptors to positive ions, rapid loss of membrane potential and extensive excitation.
The rapid component of most excitatory postsynaptic potentials (EPSP) could be accounted for by activation of AMPA glutamate receptors, which perform ‘fast’ synaptic transmission in the central nervous system and might be crucial contributors to injury [555, 585, 694, 671]. Depolarization also favors chloride ions to enter into neurons and creates an osmotic disequilibrium, driving water into neurons and producing cell edema [1045]. Ionotropic glu-tamate NMDA receptors have at least an equal, if not higher, permeability to K + as to Na+, though their permeability to Ca2+ is several folds higher than to Na+ or K + and activation of NMDA receptors potently induce cell damage [555, 1386]. Metabotropic glutamate receptors are coupled with G proteins, consisting of, at least, eight subtypes. Each subtype controls a specific metabolic path and has a unique role [743]. Activation of G proteins may potentiate NMDA and AMPA receptors [1290] and control cell behaviors through regulation of metabolic pathways right up to involving the genetic information [315, 1333]. This connection is essential, since it ensures change in connectivity of gap junctions, in production of the second and retrograde messengers, inositol trisphosphate turnover, intracellular Ca2+ and protein kinases. G proteins thus connect extra- and intracellular environments and can reorganize ion homeostasis of neurons. They can exert either stimulatory (Gs) or inhibitory (Gj) action on metabolic pathways and so support equilibrium around an optimum [504, 520, 462, 200, 443]. A powerful apparatus of G proteins promotes cell survival and determines mental health. Dysfunction of multiple neurotransmitter and neuropeptide G protein-coupled receptors in frontal cortex and limbic-related regions, such as the hippocampus, hypothala-mus and brainstem, likely underlies the complex clinical picture of psychiatric illnesses that includes cognitive, perceptual and affective symptoms. Thus, the same biochemic machine regulates cell damage and psychics.
Because excessive excitation usually causes cell damage, escaping of excitation typically protects neurons from neuronal death. Damage can be prevented by inhibitory neurotransmitters, by antagonists to various excitatory amino acids, by hyperpolarization, by K + channel openers and by Ca2+ or Na+ channel blockers [295, 573, 1085, 585, 783, 671].
In contrast to the ionic mechanism of necrosis that involves Ca2+ influx and intracellular Ca2+ accumulation, excessive K + efflux and intracellular K + depletion are key early steps in apoptosis [1386], although necrotic cells also lost their Ca2+. High concentration of intracellular K + is a distinctive feature of any cell. Physiological concentration of intracellular K + acts as a re-pressor of apoptotic effectors, at the same time as a massive loss of cellular K+ may serve as a disaster signal allowing the execution of the suicide program. Cellular K + loss stimulates post-translational maturation and release of the inflammatory factor interleukin 1. However, although cellular K + depletion is important in apoptosis, in many cases particular apoptotic activating signals act together with low K + to initiate the death program [1386]. Astrocytes play an essential role in the maintenance and protection of the brain and can sense the extracellular K+ concentration. During injury, neurons lack intracellular K + and its concentration in the extracellular space increase, but the recovery of extracellular K + is retarded because of glial toxins [733].
