Cytokines as Therapeutic Agents in Neurological Disorders

Martin, David; Relton, Jane K.; Miller, Glenn T.; Bendele, Alison M.; Fischer, Norman; Russell, D A

doi:10.1007/978-1-4615-9695-0_9

Cited by 3 publications

(5 citation statements)

References 86 publications

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“…IL_1 can also elicit an array of responses which could either inhibit, exacerbate or induce neuronal damage and death. These include induction of fever and oedema, damage to the cerebral vasculature, activation of glia, induction of neurotrophins, growth factorsÏphospholipase Aµ, cyclooxygenase (COX_2), â-amyloid precursor protein, adhesion molecules and corticotrophin-releasing factor (CRF), release of nitric oxide and other free radicals, activation of complement, and modification of calcium homeostasis (see Beneviste, 1992;Giulian et al 1993;Betz et al 1996;Martin et al 1996;Rothwell et al 1996a,c;Rothwell, 1997;Rothwell et al 1997). The infusion of IL_1á or â into the brain of normal rodents or the application to neuronal cultures, even at doses in the high nanomolar range, does not result in overt damage or death.…”

Section: Actions Of Il_1 In the Brainmentioning

confidence: 99%

“…Pattern of brain damage (shown as dark areas) in coronal brain sections of rats measured histologically 24 h after MCAo neuroprotective when administered 30-60 min after focal cerebral ischaemia and reduces not only infarct volume but also oedema, glial activation and neuronal loss, and largely reverses neurological impairment caused by MCAo (Garcia et al 1995;Relton et al 1996). In addition to these effects on MCAo in the adult rat or mouse, IL_1ra also markedly reduces brain damage caused by hypoxia/ischaemia in neonatal rats , global cerebral ischaemia in gerbils (Martin et al 1996), lateral, cortical fluid percussion injury in the rat (Toulmond & Rothwell, 1995a) and heat stroke damage in rabbits (Lin et al 1995), and reduces the clinical symptoms of experimental allergic encephalomyelitis (EAE, a rodent model of multiple sclerosis) (Martin & Near, 1995). In several of these paradigms, IL_1ra is effective when administered up to 4 h after the insult, and these actions of IL_1ra are not associated with any changes in body temperature or cardiovascular parameters in normal or brain-damaged rats.…”

Section: Functional Role Of Il_1 In Neurodegenerationmentioning

confidence: 99%

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Cytokines ‐ killers in the brain?

Rothwell

1999

The Journal of Physiology

225

103

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Section: Actions Of Il_1 In the Brainmentioning

confidence: 99%

Section: Functional Role Of Il_1 In Neurodegenerationmentioning

confidence: 99%

Cytokines ‐ killers in the brain?

Rothwell

1999

The Journal of Physiology

225

103

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“…These data indicate that IL‐1 participates directly in focal, permanent ischaemic brain damage, but further data show that inhibition of IL‐1 also markedly reduces brain damage caused by global and reversible ischaemia in adult or neonatal rodents, traumatic injury (lateral fluid percussion) (Toulmond & Rothwell, 1995), excitotoxins (N‐methyl‐D‐aspartate or AMPA/kainic agonists) (Relton & Rothwell, 1992), heat stroke (Lin et al , 1995) and clinical symptoms of experimental allergic encephalomyelitis (see Martin et al , 1996; Rothwell, 1996). Thus, IL‐1 has been implicated in diverse forms of brain damage and may influence several processes which contribute to neurodegeneration (see Rothwell, 1996).…”

Section: Cytokines and Brain Diseasementioning

confidence: 99%

Sixteenth Gaddum Memorial Lecture December 1996. Neuroimmune interactions: the role of cytokines

Rothwell

1997

British J Pharmacology

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“…In other forms of hypoxic ischemic brain damage (e.g., perinatal hypoxia in young rats and global ischemia in the gerbil), systemic administration of IL-lra also markedly reduces neuronal loss (30). Similarly, ICV or systemic injection of IL-Ira reduces damage caused by lateral fluid percussion injury in the rat (where it is effective even when first administered 4 hours after the injury) (31 ) and attenuates damage caused by heat stroke in the rabbit, excitotoxins in the rat, or EAE in the rat (30,32).…”

mentioning

confidence: 97%

“…Similarly, ICV or systemic injection of IL-Ira reduces damage caused by lateral fluid percussion injury in the rat (where it is effective even when first administered 4 hours after the injury) (31 ) and attenuates damage caused by heat stroke in the rabbit, excitotoxins in the rat, or EAE in the rat (30,32). These data provide compelling evidence for IL-1 involvement in diverse forms of acute neurodegener- ation in experimental animals.…”

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confidence: 97%

REVIEW ■ : Interleukin-1 and Neurodegeneration

Rothwell

1998

Neuroscientist

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The cytokine interleukin-1 (IL-1) has been implicated in many forms of neurodegeneration. Expression of IL-1 is increased in the brain (mainly by microglia) of animals and humans in response to acute insults (e.g., stroke and brain injury) and in chronic neurodegenerative conditions. Although IL-1 does not kill otherwise healthy neurons, small quantities of the cytokine dramatically enhance ischemic, traumatic, or excitotoxic damage in animals. Inhibition of the synthesis, release, or action of IL-1 (e.g., by administration of IL-1 receptor antagonist) markedly reduces all of these forms of experimental neurodegeneration, indicating that approaches to block or inhibit IL-1 activity may be of benefit in clinical neurodegenerative disease. NEURO-SCIENTIST 4:195-201, 1998 KEY WORDS Cytokmes, Interleukin-1, Neurodegeneration Degeneration of neurons, resulting in ultimate disability or death of the patient, is the key feature of many acute and chronic neurological diseases. These diseases include stroke, brain injury, epilepsy, Parkinson's disease and other movement disorders, multiple sclerosis, amyotrophic lateral sclerosis, and dementias, such as Alzheimer's disease, Lewy body disease, and transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob disease). Each of these conditions has very different causes, disease courses, and pathologies, but in all cases, neuronal loss is a key feature and a major determinant of morbidity and mortality. It is becoming increasingly obvious that some common mechanisms of neuronal death contribute to diverse neurodegenerative diseases. Among these common features are excessive release of excitatory amino acids and excitotoxicity, release of free radicals such as nitric oxide, disrupted intracellular ion homeostasis (particularly calcium homeostasis), and, most recently discovered, activation of immune or inflammatory processes.Brain inflammation is an accepted component of multiple sclerosis. However, although it is recognized that the immune and inflammatory responses of the CNS differ significantly from those in other tissues, many inflammatory molecules and processes are activated in most, if not all, forms of neurodegeneration. These responses include glial activation (microglia represent the primary phagocytic cell in the brain), release of eicosanoids and kinins, activation of complement, and expression of acute-phase proteins (e.g., b-amyloid precursor protein), adhesion molecules, and cytokines. This review focuses on the archetypical &dquo;proinflammatory&dquo; cytokine interleukin-1 (IL-1), because there is now considerable evidence implicating this protein in many forms of neurodegeneration.The Interleukin-1 (IL-1 ) Family IL-1, like most cytokines (Box 1), was first described as a molecule produced by peripheral immune cells involved in inflammation, yet it was probably the first cytokine shown to influence the brain as an inducer of fever (1). In fact, IL-1 comprises a family of related molecules (Fig. 1). IL-1 a and -r3, the two known agonists, share signi...

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Cytokines as Therapeutic Agents in Neurological Disorders

Cited by 3 publications

References 86 publications

Cytokines ‐ killers in the brain?

Cytokines ‐ killers in the brain?

Sixteenth Gaddum Memorial Lecture December 1996. Neuroimmune interactions: the role of cytokines

REVIEW ■ : Interleukin-1 and Neurodegeneration

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