Interactions between neural membrane glycerophospholipid and sphingolipid mediators: a recipe for neural cell survival or suicide

The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A(2) (PLA(2)) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA(2) activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA(2), modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA(2) and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA(2) and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.     

Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders

Three enzyme systems, cyclooxygenases that generate prostaglandins, lipoxygenases that form hydroxy derivatives and leukotrienes, and epoxygenases that give rise to epoxyeicosatrienoic products, metabolize arachidonic acid after its release from neural membrane phospholipids by the action of phospholipase A(2). Lysophospholipids, the other products of phospholipase A(2) reactions, are either reacylated or metabolized to platelet-activating factor. Under normal conditions, these metabolites play important roles in synaptic function, cerebral blood flow regulation, apoptosis, angiogenesis, and gene expression. Increased activities of cyclooxygenases, lipoxygenases, and epoxygenases under pathological situations such as ischemia, epilepsy, Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease produce neuroinflammation involving vasodilation and vasoconstriction, platelet aggregation, leukocyte chemotaxis and release of cytokines, and oxidative stress. These are closely associated with the neural cell injury which occurs in these neurological conditions. The metabolic products of docosahexaenoic acid, through these enzymes, generate a new class of lipid mediators, namely docosatrienes and resolvins. These metabolites antagonize the effect of metabolites derived from arachidonic acid. Recent studies provide insight into how these arachidonic acid metabolites interact with each other and other bioactive mediators such as platelet-activating factor, endocannabinoids, and docosatrienes under normal and pathological conditions. Here, we review present knowledge of the functions of cyclooxygenases, lipoxygenases, and epoxygenases in brain and their association with neurodegenerative diseases.     

Inhibitors of intracellular phospholipase A2 activity: their neurochemical effects and therapeutical importance for neurological disorders.

Intracellular phospholipases A2 (PLA2) are a diverse group of enzymes with a growing number of members. These enzymes hydrolyze membrane phospholipids into fatty acid and lysophospholipids. These lipid products may serve as intracellular second messengers or can be further metabolized to potent inflammatory mediators, such as eicosanoids and platelet-activating factors. Several inhibitors of nonneural intracellular PLA2 have been recently discovered. However, nothing is known about their neurochemical effects, mechanism of action or toxicity in human or animal models of neurological disorders. Elevated intracellular PLA2 activities, found in neurological disorders strongly associated with inflammation and oxidative stress (ischemia, spinal cord injury, and Alzheimer's disease), can be treated with specific, potent and nontoxic inhibitors of PLA2 that can cross blood-brain barrier without harm. Currently, potent intracellular PLA2 inhibitors are not available for clinical use in human or animal models of neurological disorders, but studies on this interesting topic are beginning to emerge. The use of nonspecific intracellular PLA2 inhibitors (quinacrine, heparin, gangliosides, vitamin E) in animal model studies of neurological disorders in vivo has provided some useful information on tolerance, toxicity, and effectiveness of these compounds.     

Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.     

Prostanoid signaling: dual role for prostaglandin E2 in neurotoxicity

The prostanoids, a naturally occurring subclass of eicosanoids, are lipid mediators generated through oxidative pathways from arachidonic acid. These cyclooxygenase metabolites, consisting of the prostaglandins (PG), prostacyclin and tromboxane, are released in response to a variety of physiological and pathological stimuli in almost all organs, including the brain. They are produced by various cell types and act upon targeted cells via specific G protein-coupled receptors. The existence of multiple receptors, cross-reactivity and coupling to different signal transduction pathways for each prostanoid, collectively establish their diverse effects. Notably, these effects can occur in functionally opposing directions within the same cell or organ. Prostaglandin E(2) (PGE(2)) is the most versatile prostanoid because of its receptors, E Prostanoid (EP) receptor subtypes 1 through 4, its biological heterogeneity and its differential expression on neuronal and glial cells throughout the central nervous system. Since PGE(2) plays an important role in processes associated with various neurological diseases, this review focuses on its dual neuroprotective and neurotoxic role in EP receptor subtype signaling pathways in different models of brain injury.     

Lipid mediators and their metabolism in the nucleous: implications for Alzheimer's disease

Lipid mediators are important endogenous regulators derived from enzymatic degradation of glycerophospholipids, sphingolipids, and cholesterol by phospholipases, sphingomyelinases, and cytochrome P450 hydroxylases, respectively. In neural cells, lipid mediators are associated with proliferation, differentiation, oxidative stress, inflammation, and apoptosis. A major group of lipid mediators, which originates from the enzymatic oxidation of arachidonic acid, is called eicosanoids (i.e., prostaglandins, leukotrienes, thromboxanes, and lipoxins). The corresponding lipid mediators of docosahexaenoic acid metabolism are named as docosanoids. They include resolvins, protectins (neuroprotectins), and maresins. Docosanoids produce antioxidant, anti-inflammatory, and antiapoptotic effects in brain tissue. Other glycerophospholipid-derived lipid mediators are platelet activating factor, lysophosphatidic acid, and endocannabinoids. Degradation of sphingolipids also results in the generation of sphingolipid-derived lipid mediators, such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These mediators are involved in differentiation, growth, cell migration, and apoptosis. Similarly, cholesterol-derived lipid mediators, hydroxycholesterol, produce apoptosis. Abnormal metabolism of lipid mediators may be closely associated with pathogenesis of Alzheimer's disease.     

Modulation of D1-like dopamine receptor function by aldehydic products of lipid peroxidation

Growing evidence indicates that aldehydic products of lipid peroxidation play an important role in the pathophysiology of neurodegenerative disorders such as Parkinson's disease. In the present study, modulation of D1-like receptor binding and function by saturated alkanals and unsaturated alkenals, 4-hydroxynonenal (4-HNE) and trans-2-nonenal (nonenal), was examined in rat striatal membranes. The 4-HNE and nonenal were most effective in modulating both the specific D1-like receptor binding and function as measured by adenylate cyclase activation. Inactivation of receptor binding and the depression of adenylate cyclase activity were partially prevented by protection of the D1/D5-receptor with the agonist (R)-SKF 38393 or the specific antagonist SCH 23390. 4-HNE inhibited adenylate cyclase activation by Gpp (NH)p and forskolin, indicating the modulation of Gsalpha and the catalytic subunit of adenylate cyclase, respectively. Our data suggests that aldehydic products of lipid peroxidation can directly modulate the binding and functional properties of D1/D5 receptors, as well as effector proteins within their signaling pathway.     

Peripheral benzodiazepine receptor ligand PK11195 reduces microglial activation and neuronal death in quinolinic acid-injected rat striatum

The effects of the peripheral benzodiazepine receptor (PBR) ligand, PK11195, were investigated in the rat striatum following the administration of quinolinic acid (QUIN). Intrastriatal QUIN injection caused an increase of PBR expression in the lesioned striatum as demonstrated by immunohistochemical analysis. Double immunofluorescent staining indicated PBR was primarily expressed in ED1-immunoreactive microglia but not in GFAP-immunoreactive astrocytes or NeuN-immunoreactive neurons. PK11195 treatment significantly reduced the level of microglial activation and the expression of pro-inflammatory cytokines and iNOS in QUIN-injected striatum. Oxidative-mediated striatal QUIN damage, characterized by increased expression of markers for lipid peroxidation (4-HNE) and oxidative DNA damage (8-OHdG), was significantly diminished by PK11195 administration. Furthermore, intrastriatal injection of PK11195 with QUIN significantly reduced striatal lesions induced by the excitatory amino acid and diminished QUIN-mediated caspase-3 activation in striatal neurons. These results suggest that inflammatory responses from activated microglia are damaging to striatal neurons and pharmacological targeting of PBR in microglia may be an effective strategy in protecting neurons in neurological disorders such as Huntington's disease.     

Inflammatory mediators in demyelinating disorders of the CNS and PNS

Work in both experimental models and human disorders of the central and peripheral nervous system has delineated multiple effector mechanisms that operate to produce inflammatory demyelination. The role of various soluble inflammatory mediators generated and released by both blood-borne and resident cells in this process will be reviewed. Cytokines such as interleukin (IL)-1, interferon (IFN)-γ, and tumor necrosis factor (TNF)- are pivotal in orchestrating immune and inflammatory cell-cell interactions and represent potentially noxious molecules to the myelin sheath, Schwann cells, and/or oligodendrocytes. Arachidonic acid metabolites, synthesized by and liberated from astrocytes, microglial cells and macrophages, are intimately involved in the inflammatory process by enhancing vascular permeability, providing chemotactic signals and modulating inflammatory cell activities. Reactive oxygen species can damage myelin by lipid peroxidation and may be cytotoxic to myelin-producing cells. They are released from macrophages and microglial cells in response to inflammatory cytokines. Activation of complement yields a number of inflammatory mediators and results in the assembly of the membrane attack complex that inserts into the meylin sheath-creating pores. Activated complement may contribute both to functional disturbance of neural impulse propagation, and to full-blown demyelination. Proteases, abundantly present at inflammatory foci, can degrade myelin. Vasoactive amines may play an important role in breaching of the blood-brain/blood-nerve barrier. The importance of nitric oxide metabolites in inflammatory demyelination merits investigation. A better understanding of the multiple effector mechanisms operating in inflammatory demyelination may help to devise more efficacious antigen non-specific therapy.     

Hydrogen Sulfide Scavenges the Cytotoxic Lipid Oxidation Product 4-HNE

Highly reactive α,β-unsaturated aldehydes like 4-hydroxy-2-nonenal (4-HNE), generated from oxidation of polyunsaturated fatty acids, can bind to proteins, polynucleotides and exert cytotoxicity. 4-HNE is known to react readily with thiol and amino groups on free or bound amino acids. Recently, hydrogen sulfide (H₂S) has been identified as an endogenous vascular gasotransmitter and neuromodulator which can reach up to 160 μmol/l in the brain. Markedly higher 4-HNE concentrations were reported in the brain of patients suffering from Alzheimer’s disease. Assuming that the low molecular thiol H₂S may react with 4-HNE, we have tested the ability of H₂S to counteract the cytotoxic and protein-modifying activity of 4-HNE. The results show that H₂S at physiologically relevant concentrations could effectively protect neuronal cells (SH-SY5Y) from the cytotoxic action of 4-HNE. The HNE-modification of cellular proteins was also inhibited in presence of H₂S. These data suggest that H₂S may be an important protective factor against carbonyl stress by inactivating/modulating the action of highly reactive α,β-unsaturated aldehydes like 4-HNE in the brain.     

Stem cell‐based cell therapy in neurological diseases: A review

Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell‐based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell‐based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell‐based cell therapies for neurological diseases. © 2009 Wiley‐Liss, Inc.     

Glutamate signalling and secretory phospholipase A2 modulate the release of arachidonic acid from neuronal membranes

The lipid mediators generated by phospholipases A(2) (PLA(2)), free arachidonic acid (AA), eicosanoids, and platelet-activating factor, modulate neuronal activity; when overproduced, some of them become potent neurotoxins. We have shown, using primary cortical neuron cultures, that glutamate and secretory PLA(2) (sPLA(2)) from bee venom (bv sPLA(2)) and Taipan snake venom (OS2) elicit synergy in inducing neuronal cell death. Low concentrations of sPLA(2) are selective ligands of cell-surface sPLA(2) receptors. We investigated which neuronal arachidonoyl phospholipids are targeted by glutamate-activated cytosolic calcium-dependent PLA(2) (cPLA(2)) and by sPLA(2). Treatment of (3)H-AA-labeled cortical neurons with mildly toxic concentrations of sPLA(2) (25 ng/ml, 1.78 nM) for 45 min resulted in a two- to threefold higher loss of (3)H-AA from phosphatidylcholine (PC) than from phosphatidylethanolamine (PE) and in minor changes in other phospholipids. A similar profile, although of greater magnitude, was observed 20 hr posttreatment. Glutamate (80 microM) induced much less mobilization of (3)H-AA than did sPLA(2) and resulted in a threefold greater degradation of (3)H-AA PE than of (3)H-AA PC by 20 hr posttreatment. Combining sPLA(2) and glutamate resulted in a greater degradation of PC and PE, and the N-methyl-D-aspartate receptor antagonist MK-801 only blocked glutamate effects. Thus, activation of the arachidonate cascade induced by glutamate and sPLA(2) under experimental conditions that lead to neuronal cell death involves the hydrolysis of different (perhaps partially overlapping) cellular phospholipid pools.     

Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function.     

Inhibitors of intracellular phospholipase A2 activity: their neurochemical effects and therapeutical importance for neurological disorders

Intracellular phospholipases A₂ (PLA₂) are a diverse group of enzymes with a growing number of members. These enzymes hydrolyze membrane phospholipids into fatty acid and lysophospholipids. These lipid products may serve as intracellular second messengers or can be further metabolized to potent inflammatory mediators, such as eicosanoids and platelet-activating factors. Several inhibitors of nonneural intracellular PLA₂ have been recently discovered. However, nothing is known about their neurochemical effects, mechanism of action or toxicity in human or animal models of neurological disorders. Elevated intracellular PLA₂ activities, found in neurological disorders strongly associated with inflammation and oxidative stress (ischemia, spinal cord injury, and Alzheimer’s disease), can be treated with specific, potent and nontoxic inhibitors of PLA₂ that can cross blood–brain barrier without harm. Currently, potent intracellular PLA₂ inhibitors are not available for clinical use in human or animal models of neurological disorders, but studies on this interesting topic are beginning to emerge. The use of nonspecific intracellular PLA₂ inhibitors (quinacrine, heparin, gangliosides, vitamin E) in animal model studies of neurological disorders in vivo has provided some useful information on tolerance, toxicity, and effectiveness of these compounds.     

4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and Aberrant Axonal Outgrowth in Adult Sensory Neurons that Mimics Features of Diabetic Neuropathy

Modification of proteins by 4-hydroxy-2-nonenal (4-HNE) has been proposed to cause neurotoxicity in a number of neurodegenerative diseases, including distal axonopathy in diabetic sensory neuropathy. We tested the hypothesis that exposure of cultured adult rat sensory neurons to 4-HNE would result in the formation of amino acid adducts on mitochondrial proteins and that this process would be associated with impaired mitochondrial function and axonal regeneration. In addition, we compared 4-HNE-induced axon pathology with that exhibited by neurons isolated from diabetic rats. Cultured adult rat dorsal root ganglion (DRG) sensory neurons were incubated with varying concentrations of 4-HNE. Cell survival, axonal morphology, and level of axon outgrowth were assessed. In addition, video microscopy of live cells, western blot, and immunofluorescent staining were utilized to detect protein adduct formation by 4-HNE and to localize actively respiring mitochondria. 4-HNE induced formation of protein adducts on cytoskeletal and mitochondrial proteins, and impaired axon regeneration by approximately 50% at 3 μM while having no effect on neuronal survival. 4-HNE initiated formation of aberrant axonal structures and caused the accumulation of mitochondria in these dystrophic structures. Neurons treated with 4-HNE exhibited a distal loss of active mitochondria. Finally, the distal axonopathy and the associated aberrant axonal structures generated by 4-HNE treatment mimicked axon pathology observed in DRG sensory neurons isolated from diabetic rats and replicated aspects of neurodegeneration observed in human diabetic sensory neuropathy.     

苯丙氨酸及其代谢物对P19细胞神经分化的影响

探讨苯丙氨酸及其代谢物对P19细胞分化的影响及机制。实验各组从P19细胞神经分化诱导期开始分别加入苯丙氨酸、苯乙酸和苯乳酸 ,观察神经分化期细胞形态 ,MTT法检测神经分化期细胞存活率和LDH漏出量的变化 ,并通过流式细胞仪检测诱导后细胞周期有无变化。结果显示 :苯丙氨酸及其代谢物可使P19神经元肿胀、崩解 ,神经突起纤细且突起数少 ,可降低P19细胞存活率 ,但对LDH漏出量并无影响 ,对诱导后的P19细胞周期也无影响。以上结果提示 ,苯丙氨酸及其代谢物可干扰P19细胞的神经诱导过程 ,母源性苯丙酮尿症中枢神经系统损伤可能与其在脑发育早期阶段神经诱导及分化过程中受到高苯丙氨酸及其代谢物影响有关。     

Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A2 inhibitors

In kainate-induced neurotoxicity, the stimulation of kainate receptors results in the activation of phospholipase A₂ and a rapid release of arachidonic acid from neural membrane glycerophospholipids. This process raises arachidonic acid levels and produces alterations in membrane fluidity and permeability. These result in calcium influx and stimulation of lipolysis and proteolysis, production of lipid peroxides, depletion of ATP, and loss of reduced glutathione. As well as the above neurochemical changes, stimulation of ornithine decarboxylase, altered activities of protein kinase C isozymes, and expression of immediate early genes, cytokines, growth factors, and heat shock proteins have also been reported. Kainate-induced stimulation of arachidonic acid release, calcium influx, accumulation of lipid peroxides and products of their decomposition, especially 4-hydroxynonenal (4-HNE), along with alterations in cellular redox state and ATP depletion may play important roles in kainate-induced cell death. Thus the consequences of altered glycerophospholipid metabolism in kainate-induced neurotoxicity can lead to cell death. Kainate-induced neurotoxicity initiates apoptotic as well as necrotic cell death depending upon the intensity of oxidative stress and abnormality in mitochondrial function. Other neurochemical changes may be related to synaptic reorganization following kainate-induced seizures and may be involved in recapitulation of hippocampal development and synaptogenesis.     

Ferroptosis,a Recent Defined Form of Critical Cell Death in Neurological Disorders

Ferroptosis is a recently defined form of cell death with the involvement of iron and reactive oxygen species (ROS), which is distinct from apoptosis, autophagy and other forms of cell death. Emerging evidence suggested that iron accumulation and lipid peroxidation can be discovered in various neurological diseases, accompanied with reduction of glutathione (GSH) and glutathione peroxidase 4 (GPX4). In addition, ferroptotic inhibitors have been shown to protect neurons, and recover the cognitive function in disease animal models. This review summarizes the mechanisms underlying ferroptosis and reviews the contributions of ferroptosis in neurodegenerative diseases (i.e. Alzheimer’s disease and Parkinson’s disease), traumatic brain injury, as well as hemorrhagic and ischemic stroke, to provide the current understanding of this novel form of cell death in neurological disorders.