Stroke is a leading cause of serious, long-term disability in the world. Every 45 seconds someone is affected by stroke and on average every 3–4 min someone dies of focal ischemia. In fact, 15 million people suffer from stroke worldwide each year. Of these, five million die and another five million are permanently disabled. Stroke ranks among the third most common cause of death after heart disease and cancer. In developed countries, the incidence of stroke is declining – largely because of the efforts to lower blood pressure and reduce smoking. However, given that age is one of the most substantiated risk factors for stroke, the aging of the world population implies a growing number of people at risk.
The mean lifetime cost of a single ischemic stroke in the US is estimated at $140,048, including impatient care, rehabilitation, and follow-up care for longlasting deficits. The estimated direct and indirect costs of stroke for 2009 are $ 68.9 billion in the United States and $ 32.3 billion in the European Union countries.
Stroke is caused by a blood clot that lodges in the brain and reduces oxygen supply to critical tissue. Two general therapeutic approaches are available: the first strategy is aimed at reducing the failure of arterial oxygen and glucose delivery to the local brain tissue by performing a thrombolysis of the arterial thrombus within few hours from the onset of symptoms and to reduce the tissue back-pressure occurring when failure of the blood–brain-barrier causes vasogenic edema. The second, not yet validated, therapeutical strategy is to exert a neuroprotective action on the surviving brain ischemic tissue.
Despite the great effort generated in the attempt to identify new pharmacological treatments, the only current drug therapy used in the treatment of stroke belongs to the first thrombolytic strategy. However, this pharmacological approach has a narrow window of time for therapeutic application and dose-limiting adverse effects. In fact, the clot busting drug recombinant tPA can save lives and diminish disability, but its use is limited to about 3–4% of all stroke patients. In part, this is because the drug must be administered within 3 hours after the beginning of stroke symptomatology. Furthermore, tPA has also risky side effects such as haemorrhage, edema, and potential neurotoxic effects have been hypothesized by some experimental studies.
Rupture or blockade of a blood vessel in the brain causes rapid cell death in the core of the injured region and triggers mechanisms in the surrounding area – the penumbra – that lead among several mediators to changes in the concentrations of several ions such as intracellular Ca2+, Na+, H+, K+, and radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). All these transductional factorsmight initiate cell death. In particular, it is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is the progressive accumulation of intracellular Na+ ions, which can precipitate necrosis and apoptosis of vulnerable neurons. Whereas the detrimental action of [Na+]i increase is attributable to both cell swelling and microtubular disorganization – phenomena that lead to cell necrosis – a change in Ca2+,Na+, K+, H+ ions has been shown to be a key factor in ischemic brain damage, for it modulates several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, protease activation, and apoptosis.
SinceOlney’s seminal work firstly suggested that excitatory amino acids could elicit neurotoxicity, a large amount of work has been accumulated showing that glutamate extracellular concentrations briskly rise during acute brain injury, thus triggering an influx of Ca2+ and Na+ ions into neurons through ionotropic glutamate receptor subtypes. This evidence has led to the elaboration of the paradigm of glutamate excitotoxicity that explains ischemic neuronal cell death as a mere consequence of Na+ and Ca2+ influx through glutamate receptors.
Although this theory has been guiding basic research in the field of neurodegeneration for almost three decades, more recently it has become the object of serious criticism and reassessment. What has aroused such skepticism among researchers has been the fact that although first, second, and third generation glutamate receptor antagonists have long yielded promising results in animal models of brain ischemia, they have failed to elicit a neuroprotective action in stroke and traumatic brain injury in humans. Therefore, the theory of excitotoxicity, though a fascinating paradigm, can only explain some of the events occurring in the acute phase of anoxic insult but cannot be seen as a major target for developing new therapeutic avenues for brain ischemia.
In the last decade, several seminal experimental works are markedly changing the scenario in this field. In fact, it has been shown that some integral plasma-membrane proteins, involved in the control of Ca2+, Na+, K+, H+ ions influx or efflux and, therefore, responsible for maintaining the homeostasis of these four cations, might function as crucial players in the brain ischemic process. Indeed, these proteins, by regulating Ca2+, Na+, K+, H+ homeostasis, may provide the molecular basis underlying glutamateindependent Ca2+ overload mechanisms in neuronal ischemic cell death and, most importantly, may represent more suitable molecular targets for therapeutic intervention. Targeting these mechanisms is a promising route for the development of innovative therapies for stroke treatments.
The main goal of this book is to provide readers involved in basic and clinical research with an overview of glutamate receptor-independent channels, pumps, and ionic exchangers regulating Na+ and Ca2+ homeostasis, involved in the pathophysiology of the ischemic damage and potentially targetable in the attempt to develop a new therapy in stroke intervention.
Twelve chapters are included in this book. Chapter ‘‘Basis of ionic dysregulation in cerebral ischemia’’ describes the basis of ionic dysregulation in cerebral ischemia. Chapter ‘‘Why have ionotropic and metabotropic glutamate antagonists failed in stroke therapy?’’ summarizes the reasons of the failure of the glutamate theory. Chapters ‘‘Mitochondrial channels as potential target for a pharmacological strategies in brain ischemia’’ and ‘‘Endoplasmic reticulum calcium homeostasis and neuronal pathophysiology of stroke’’ deal with the role of the two intracellular organelles, mitochondria and endoplasmic reticulum, in the pathophysiology of the ischemic event. The subsequent four chapters of the book, chapters ‘‘The Naþ/Ca2þ exchanger: a target for therapeutic intervention in cerebral ischemia’’, ‘‘The ‘loop’ diuretic drug bumetanide-sensitive Naþ-Kþ-Cl– cotransporter in cerebral ischemia’’, ‘‘The Naþ/Hþ exchanger: A target for therapeutic intervention in cerebral ischemia’’, and ‘‘The Naþ/Kþ-ATPase as a drug target for ischemic stroke’’, present data regarding the potential involvement of ionic transporters responsible for the control of neuronal ionic homeostasis in the development of stroke lesion. In particular, the following transporters are described: Naþ/Ca2þ exchangers, NCXs, Na+/K+/Ca2+/Cl– cotransporters, NKCCs, Na+/H+ Exchangers, NHEs, andNaþ/Kþ ATPase.
In the second part of the book, chapters ‘‘Acid-sensing ion channels (ASICs): New targets in stroke treatment’’, ‘‘Role of TRPM7 in ischemic CNS injury’’, ‘‘Subtypes of voltage-gated Ca2+ channels and ischemic brain injury’’, and ‘‘The diverse roles of K+ channels in brain ischemia’’, it is described the role of important membrane ionic channels such as Acid-Sensing Ionic Channels, ASIC, the Transient Receptor Potential Channels, TRPC; Voltage Operated Ca2+ Channels, VOCC and K+ channels.
Each chapter dedicated to most of the molecular targets involved in the maintenance of ionic homeostasis describes in a coordinated way the relevant information related to:
The mean lifetime cost of a single ischemic stroke in the US is estimated at $140,048, including impatient care, rehabilitation, and follow-up care for longlasting deficits. The estimated direct and indirect costs of stroke for 2009 are $ 68.9 billion in the United States and $ 32.3 billion in the European Union countries.
Stroke is caused by a blood clot that lodges in the brain and reduces oxygen supply to critical tissue. Two general therapeutic approaches are available: the first strategy is aimed at reducing the failure of arterial oxygen and glucose delivery to the local brain tissue by performing a thrombolysis of the arterial thrombus within few hours from the onset of symptoms and to reduce the tissue back-pressure occurring when failure of the blood–brain-barrier causes vasogenic edema. The second, not yet validated, therapeutical strategy is to exert a neuroprotective action on the surviving brain ischemic tissue.
Despite the great effort generated in the attempt to identify new pharmacological treatments, the only current drug therapy used in the treatment of stroke belongs to the first thrombolytic strategy. However, this pharmacological approach has a narrow window of time for therapeutic application and dose-limiting adverse effects. In fact, the clot busting drug recombinant tPA can save lives and diminish disability, but its use is limited to about 3–4% of all stroke patients. In part, this is because the drug must be administered within 3 hours after the beginning of stroke symptomatology. Furthermore, tPA has also risky side effects such as haemorrhage, edema, and potential neurotoxic effects have been hypothesized by some experimental studies.
Rupture or blockade of a blood vessel in the brain causes rapid cell death in the core of the injured region and triggers mechanisms in the surrounding area – the penumbra – that lead among several mediators to changes in the concentrations of several ions such as intracellular Ca2+, Na+, H+, K+, and radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). All these transductional factorsmight initiate cell death. In particular, it is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is the progressive accumulation of intracellular Na+ ions, which can precipitate necrosis and apoptosis of vulnerable neurons. Whereas the detrimental action of [Na+]i increase is attributable to both cell swelling and microtubular disorganization – phenomena that lead to cell necrosis – a change in Ca2+,Na+, K+, H+ ions has been shown to be a key factor in ischemic brain damage, for it modulates several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, protease activation, and apoptosis.
SinceOlney’s seminal work firstly suggested that excitatory amino acids could elicit neurotoxicity, a large amount of work has been accumulated showing that glutamate extracellular concentrations briskly rise during acute brain injury, thus triggering an influx of Ca2+ and Na+ ions into neurons through ionotropic glutamate receptor subtypes. This evidence has led to the elaboration of the paradigm of glutamate excitotoxicity that explains ischemic neuronal cell death as a mere consequence of Na+ and Ca2+ influx through glutamate receptors.
Although this theory has been guiding basic research in the field of neurodegeneration for almost three decades, more recently it has become the object of serious criticism and reassessment. What has aroused such skepticism among researchers has been the fact that although first, second, and third generation glutamate receptor antagonists have long yielded promising results in animal models of brain ischemia, they have failed to elicit a neuroprotective action in stroke and traumatic brain injury in humans. Therefore, the theory of excitotoxicity, though a fascinating paradigm, can only explain some of the events occurring in the acute phase of anoxic insult but cannot be seen as a major target for developing new therapeutic avenues for brain ischemia.
In the last decade, several seminal experimental works are markedly changing the scenario in this field. In fact, it has been shown that some integral plasma-membrane proteins, involved in the control of Ca2+, Na+, K+, H+ ions influx or efflux and, therefore, responsible for maintaining the homeostasis of these four cations, might function as crucial players in the brain ischemic process. Indeed, these proteins, by regulating Ca2+, Na+, K+, H+ homeostasis, may provide the molecular basis underlying glutamateindependent Ca2+ overload mechanisms in neuronal ischemic cell death and, most importantly, may represent more suitable molecular targets for therapeutic intervention. Targeting these mechanisms is a promising route for the development of innovative therapies for stroke treatments.
The main goal of this book is to provide readers involved in basic and clinical research with an overview of glutamate receptor-independent channels, pumps, and ionic exchangers regulating Na+ and Ca2+ homeostasis, involved in the pathophysiology of the ischemic damage and potentially targetable in the attempt to develop a new therapy in stroke intervention.
Twelve chapters are included in this book. Chapter ‘‘Basis of ionic dysregulation in cerebral ischemia’’ describes the basis of ionic dysregulation in cerebral ischemia. Chapter ‘‘Why have ionotropic and metabotropic glutamate antagonists failed in stroke therapy?’’ summarizes the reasons of the failure of the glutamate theory. Chapters ‘‘Mitochondrial channels as potential target for a pharmacological strategies in brain ischemia’’ and ‘‘Endoplasmic reticulum calcium homeostasis and neuronal pathophysiology of stroke’’ deal with the role of the two intracellular organelles, mitochondria and endoplasmic reticulum, in the pathophysiology of the ischemic event. The subsequent four chapters of the book, chapters ‘‘The Naþ/Ca2þ exchanger: a target for therapeutic intervention in cerebral ischemia’’, ‘‘The ‘loop’ diuretic drug bumetanide-sensitive Naþ-Kþ-Cl– cotransporter in cerebral ischemia’’, ‘‘The Naþ/Hþ exchanger: A target for therapeutic intervention in cerebral ischemia’’, and ‘‘The Naþ/Kþ-ATPase as a drug target for ischemic stroke’’, present data regarding the potential involvement of ionic transporters responsible for the control of neuronal ionic homeostasis in the development of stroke lesion. In particular, the following transporters are described: Naþ/Ca2þ exchangers, NCXs, Na+/K+/Ca2+/Cl– cotransporters, NKCCs, Na+/H+ Exchangers, NHEs, andNaþ/Kþ ATPase.
In the second part of the book, chapters ‘‘Acid-sensing ion channels (ASICs): New targets in stroke treatment’’, ‘‘Role of TRPM7 in ischemic CNS injury’’, ‘‘Subtypes of voltage-gated Ca2+ channels and ischemic brain injury’’, and ‘‘The diverse roles of K+ channels in brain ischemia’’, it is described the role of important membrane ionic channels such as Acid-Sensing Ionic Channels, ASIC, the Transient Receptor Potential Channels, TRPC; Voltage Operated Ca2+ Channels, VOCC and K+ channels.
Each chapter dedicated to most of the molecular targets involved in the maintenance of ionic homeostasis describes in a coordinated way the relevant information related to:
(1) gene structure,
(2) structural features,
(3) molecular biology,
(4) cellular and tissue distribution,
(5) biophysical and electrophysiological properties,
(6) receptorial, transcriptional and transductional regulatory mechanisms,
(7) physiological properties,
(8) pathophysiological relevance in stroke,
(9) pharmacological modulation,
(10) preliminary clinical trials, and
(11) therapeutic perspectives.
This book written by the most authoritative scientists in the field should provide to the readers the most relevant information to understand the role played by the most recently discovered mechanisms involved in the pathophysiology of stroke thus providing the characterization of new pharmacological avenues for the cure of this relevant neurological disease.
Contents
This book written by the most authoritative scientists in the field should provide to the readers the most relevant information to understand the role played by the most recently discovered mechanisms involved in the pathophysiology of stroke thus providing the characterization of new pharmacological avenues for the cure of this relevant neurological disease.
Contents
- Basis of Ionic Dysregulation in Cerebral Ischemia
- Why have Ionotropic and Metabotropic Glutamate Antagonists Failed in Stroke Therapy?
- Mitochondrial Channels as Potential Targets for Pharmacological Strategies in Brain Ischemia
- Endoplasmic Reticulum Calcium Homeostasis and Neuronal Pathophysiology of Stroke
- The Naþ/Ca2þ Exchanger: A Target for Therapeutic Intervention in Cerebral Ischemia
- The ‘‘Loop’’ Diuretic Drug Bumetanide-Sensitive Naþ-Kþ-Cl–Cotransporter in Cerebral Ischemia
- The Naþ/Hþ Exchanger: A Target for Therapeutic Intervention in Cerebral Ischemia
- The Naþ/Kþ-ATPase as a Drug Target for Ischemic Stroke
- Acid-Sensing Ion Channels (ASICs): New Targets in Stroke Treatment
- Role of TRPM7 in Ischemic CNS Injury
- Subtypes of Voltage-Gated Ca2þ Channels and Ischemic Brain Injury
- The Diverse Roles of Kþ Channels in Brain Ischemia
- Clinical Trials with Drugs Targeting Ionic Channels, Antiporters, and Pumps in Ischemic Stroke
Index