The Handbook of Neuroprotection

865 Pages·2019·7.844 MB·English

by  Kewal K. Jain

Kewal K. Jain
T he
Handbook of
Neuroprotection
Second Edition
The Handbook of Neuroprotection
The Handbook
of Neuroprotection
Second Edition
Kewal K. Jain, MD, FRACS, FFPM
Jain PharmaBiotech, Basel, Switzerland
Kewal K. Jain
Jain PharmaBiotech
Basel, Switzerland
ISBN 978-1-4939-9464-9 ISBN 978-1-4939-9465-6 (eBook)
https://doi.org/10.1007/978-1-4939-9465-6
© Springer Science+Business Media, LLC, part of Springer Nature 2011, 2019
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Preface to the Second Edition
Recognition of the importance of neuroprotection in the management of neurologi-
cal disorders has steadily increased during the past decade. Considerable progress
has been made in this area since the publication of the first edition in 2011. Advances
in biotechnology, particularly in cell and gene therapies, have provided several new
products for neuroprotection. Some of the old products in clinical trials failed to
show efficacy, and these are still retained in the book, while new products in clinical
trials are listed. Neuroprotective effect of some drugs approved for other indications
is also included as their repurposing is much easier than developing a new drug.
This book reviews management of neurological disorders with a focus on neuro-
protection and disease modification rather than symptomatic treatment.
Neurodegenerative disorders present with considerable damage by the time they are
diagnosed, and the aim is to prevent further damage and to reverse some of the dam-
age, which is a bigger challenge. This requires a combination of neuroprotection
and neuroregeneration. In the case of acute central nervous system trauma and
stroke, immediate damage is followed by a cascade of secondary events that aggra-
vate the initial insult. The aim of neuroprotection is to prevent the secondary dam-
age combined with measures to regenerate tissues of the central nervous system.
The audience for this book includes clinical neurologists, neurosurgeons, neuro-
scientists, neuropharmacologists, and companies developing drugs for CNS disor-
ders. More than half of the original content of the first edition is replaced with
addition of material based on the latest research supported by over 1000 citations
from literature that are appended after each chapter. The text is supplemented with
20 illustrations and 78 tables.
Finally, the author wishes to acknowledge the help and encouragement of the
Springer editor for this project, David C. Casey, throughout the preparation of this
book.
Basel, Switzerland Kewal K. Jain, MD
v
Preface to the First Edition
Neuroprotection is an important part of care of the neurological disorders. Treatment
of neurological disorders should not be merely symptomatic, but an effort should be
made to prevent the progression of the underlying disease and to develop therapies
for regeneration. Neuroprotection also covers the protection of the part of the ner-
vous system exposed to trauma and surgery. Neuroprotection has been used in med-
ical practice for the past 50 years. The earliest agents were barbiturates and
nonpharmacological approaches such as hypothermia and hyperbaric oxygen.
Neuroprotection has been placed on a firm scientific basis during the past decade
due to an improved understanding of the molecular basis of neurological diseases.
This book is a comprehensive review of neuroprotection based on the knowledge of
the molecular basis of neurological disorders. Neuroprotective effects of older,
established drugs as well as new drugs in development are documented.
This book has evolved over a decade, starting with a commercial report on neu-
roprotection. Although there is no cure for several neurological disorders, tremen-
dous progress has been made in understanding the pathomechanism of diseases
such as stroke and neurodegenerative disorders. Over 500 drugs are under investiga-
tion at various stages from preclinical research to clinical trials. A number of drugs
with neuroprotective effects are on the market. Further research has been done on
the older methods of neuroprotection such as hypothermia and hyperbaric oxygen.
Ongoing clinical trials of innovative methods as well as failed therapies are listed.
Basel, Switzerland Kewal K. Jain, MD
vii
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Neuroprotective Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3 Neuroprotection in Cerebrovascular Disease . . . . . . . . . . . . . . . . . . . . 175
4 Neuroprotection in Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . 281
5 Neuroprotection in Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . 337
6 Neuroprotection in Neurodegenerative Disorders . . . . . . . . . . . . . . . . 369
7 Neuroprotection in Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . 403
8 Neuroprotection in Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . 465
9 Neuroprotection in Huntington Disease . . . . . . . . . . . . . . . . . . . . . . . . 587
10 Neuroprotection in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . 609
11 Neuroprotection in Miscellaneous Neurological Disorders . . . . . . . . . 643
12 Neuroprotection of The Optic Nerve and The Retina . . . . . . . . . . . . . 767
13 N europrotection During Anesthesia and Surgery . . . . . . . . . . . . . . . . 801
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
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List of Figures
Fig. 1.1 A three-stage model of ischemic hypoxic disturbances
of the brain ........................................... 25
Fig. 2.1 Mechanism of neuroprotective effect of sigma-1
receptor agonists....................................... 60
Fig. 2.2 NMDA receptor ion channel complex. Glutamate binding
is facilitated by glycine and antagonized by competitive
antagonists............................................ 99
Fig. 2.3 Neuroprotective effect of galantamine ...................... 129
Fig. 3.1 Some steps in the ischemic cascade and site of action
of neuroprotectives ..................................... 180
Fig. 3.2 Relationship between dementia and acute ischemic stroke ...... 192
Fig. 3.3 Molecules involved in preconditioning for neuroprotection
in ischemia ........................................... 242
Fig. 3.4 A roadmap for neuroprotection............................ 270
Fig. 4.1 Cascade of events following traumatic brain injury............ 285
Fig. 4.2 Secondary injury mechanisms after TBI..................... 288
Fig. 4.3 Management of raised ICP after TBI ....................... 296
Fig. 5.1 Pathomechanism of acute spinal cord injury ................. 339
Fig. 7.1 Neuroprotective strategies against death
of dopamine-containing neurons in PD ..................... 414
Fig. 8.1 Mechanisms of Aβ clearance. Abbreviation: LRP
lipoprotein receptor-related protein, RAGE receptor
for advanced glycation end products ....................... 477
Fig. 8.2 Nitric oxide neurotoxicity and neuroprotection in relation
to Alzheimer disease.................................... 488
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xii List of Figures
Fig. 8.3 Oxidative stress and Alzheimer disease ..................... 489
Fig. 8.4 Pathomechanism of AD ................................. 498
Fig. 9.1 Role of HTT protein in pathogenesis of HD and points
of intervention......................................... 601
Fig. 11.1 Common mechanisms of neural damage in cerebral
ischemia and seizures ................................... 658
Fig. 11.2 Role of neuroprotection in epilepsy and its treatment .......... 659
List of Tables
Table 1.1 Historical landmarks in the development of neuroprotection... 3
Table 1.2 Intrinsic neuroprotective factors......................... 9
Table 1.3 Common features of pathophysiology of brain damage
in diseases.......................................... 21
Table 1.4 Place of neuroprotection in management of CNS disorders ... 28
Table 1.5 Indications for the use of neuroprotection ................. 28
Table 1.6 Neuroprotective nanoparticles .......................... 37
Table 2.1 A classification of neuroprotective agents ................. 50
Table 2.2 The neuroprotective effect of antiepileptic drugs............ 61
Table 2.3 Neuroprotective affect of minocycline in animal models...... 68
Table 2.4 Classification of antioxidants or free radical scavengers
with neuroprotective potential .......................... 79
Table 2.5 Role of erythropoietin in the nervous system............... 87
Table 2.6 Ionotropic glutamate receptors.......................... 94
Table 2.7 Classification of metabotropic glutamate receptors (mGluRs).. 95
Table 2.8 Methods for neuroprotection based on nonpharmacological
preconditioning...................................... 165
Table 3.1 Cerebrovascular diseases that are relevant to neuroprotection... 179
Table 3.2 Neuroprotective strategies for stroke ..................... 193
Table 3.3 Selected effective combinations of hypothermia with other
neuroprotective strategies for the treatment of ischemic
stroke in experimental models .......................... 239
Table 3.4 Neuroprotective gene transfer in models of cerebral ischemia .. 250
Table 3.5 Neuroprotective gene therapy in animal stroke models....... 250
Table 3.6 Neuroprotective agents in clinical development for acute
cerebrovascular disease ............................... 254
Table 3.7 Some failed trials for neuroprotective therapy for stroke...... 258
Table 3.8 Preclinical assessment of neuroprotective agents
in acute stroke models ................................ 269
Table 3.9 Stroke prevention based on control of risk factors........... 272
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