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Neuroprotection in stroke
 

Neuroprotection in stroke

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  • Stroke is the third leading cause of death in the United States and the most common cause of adult disability. An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. The only currently approved stroke therapy, tissue plasminogen activator, is a thrombolytic that targets the thrombus within the blood vessel. Neuroprotective agents, another approach to stroke treatment, have generated as much interest as thrombolytic therapies. Using various mechanisms, neuroprotective agents attempt to save ischemic neurons in the brain from irreversible injury. Studies in animals indicate a period of at least 4 hours after onset of complete ischemia in which many potentially viable neurons exist in the ischemic penumbra. In humans, the ischemia may be less complete, and the time window may be longer, but human patients also tend to be older with comorbidities that may limit benefit. As many neuroprotective drugs reduce ischemic damage in animal models of stroke, this line of pharmaceutical research holds great promise. Many are searching for a safe agent that can limit ischemic damage in human stroke. One action of neuroprotective agents limits acute injury to neurons in the penumbra region or rim of the infarct after ischemia. Neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury. Returning blood contains leukocytes that may occlude small vessels and release toxic products.
  • Stroke is the third leading cause of death in the United States and the most common cause of adult disability. An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. The only currently approved stroke therapy, tissue plasminogen activator, is a thrombolytic that targets the thrombus within the blood vessel. Neuroprotective agents, another approach to stroke treatment, have generated as much interest as thrombolytic therapies. Using various mechanisms, neuroprotective agents attempt to save ischemic neurons in the brain from irreversible injury. Studies in animals indicate a period of at least 4 hours after onset of complete ischemia in which many potentially viable neurons exist in the ischemic penumbra. In humans, the ischemia may be less complete, and the time window may be longer, but human patients also tend to be older with comorbidities that may limit benefit. As many neuroprotective drugs reduce ischemic damage in animal models of stroke, this line of pharmaceutical research holds great promise. Many are searching for a safe agent that can limit ischemic damage in human stroke. One action of neuroprotective agents limits acute injury to neurons in the penumbra region or rim of the infarct after ischemia. Neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury. Returning blood contains leukocytes that may occlude small vessels and release toxic products.
  • Free radicals generated during cerebral ischemia or reperfusion are thought to have a significant role in the development of brain injury 1 . The aim of neuroprotection in acute ischemic stroke is to preserve viable brain cells in the ischemic penumbra by interfering with the damaging events of the ischemic cascade 2 . References 1. Green AR, Ashwood A. Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord 2005; 4: 109-118. 2 . Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22: 391-397.
  • Limiting the area and impact of injury to neuronal cells in the ischemic penumbra may improve recovery from stroke 1 . Extensive research has increased the understanding of potential targets of neuroprotection during ischemia 2 . References 1. Fisher M. The ischemic penumbra: identification, evolution and treatment concepts. Cerebrovasc Dis 2004; 17 (suppl 1): 1-6. 2. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003; 4: 399-415.

Neuroprotection in stroke Neuroprotection in stroke Presentation Transcript

  • Neuroprotection in Acute Ischemic Stroke Edaravone
  • Knowing stroke
    • Stroke is a damage to a part of brain due to inadequate blood flow
    • The part of the affected brain dies and can no longer function.
      • This may be caused due to blockage or rupturing of blood vessel inside the brain
    • Risk factors – age, hypertension, IHD, genetics, smoking, drug and alcohol abuse, brain tumor, infections and blood clotting disorders
  • Identifying stroke
    • Recognize a stroke by asking 3 simple questions:
    Ask the individual to SMILE. Ask the person to TALK & say a simple sentence (Coherently) (eg. It is sunny out today) Ask him or her to RAISE both arms.
  • Identifying stroke
    • What happens in stroke?
    • How many types of stroke are there?
  • Types of Stroke
  • Types of Brain cells
    • Astrocytes
    • Microglia
    • Oligodendroglia
    • Schwann cells
    • Why must we know this?
  • Target for brain cell damage
    • Because, Oligodendroglia are the white matter cell, most susceptible to excitotoxicity in anoxic injury -> ATP depletion
    • Oligodendroglial cells express AMPA subtype of glutamate receptors.
  • Path for brain cell damage
    • Blood flow interruption -> Nutrition flow interruption -> Oxygen flow interruption -> Anoxia -> Disrupted ATP formation -> ATP depletion .
    • Core vs penumbra
      • Core
        • 0-5 minutes 10% of total
        • 5 min – 4h 25% of total
      • Penumbra
        • 50-70% normal initially then decreases to core values over time.
    • Injury -10%, Reperfusion – 75%, Recovery - 50%
  • Theories of brain cell damage Glutamate toxicity Calcium Neuro toxicity Calcium Activated Proteases and Endo-nucleases Necrosis and apoptosis Nitric oxide formation Mitochondrial dysfunction Formation of free radical species [ROS]
  • Theories of brain cell damage AMPA and NMDA are 2 types of ionotropic glutamate receptors: (AMPA =amino-3-hydroxy-5-methol-4-isoazole propionic acid) (NMDA = N-methyl –D- aspartate)
  • Schematic ischaemic cascade When the presynaptic neurone becomes ischaemic, it depolarizes opening up the Na & K channels[1,2]
  • Schematic ischaemic cascade This leads to opening of Ca channels and influx of calcium into the pre synaptic area [3]
  • Schematic ischaemic cascade In addition, the pre synaptic area releases glutamate that activates the NMDA, AMPA and MGLUR [4.5.6.7.8] This causes entry of calcium in the post synaptic area
  • Schematic ischaemic cascade This causes Nitric oxide levels to increase and ↑ perfusion. The released calcium activates various enzymes.
  • Schematic ischaemic cascade Reperfusion occurs [9] and upregulated adhesion molecules cause release of cytokines to cause inflammation [10] . Inflammation leads to release of free radicals like ROS [11] -> cell death
  • 4 constant events in Stroke
    • Anoxia = ATP decrease & pH decrease
    • Sodium influx
    • Calcium influx & ↑ Glutamate activity
    • ROS increase
  • Glutamate & Ca++ triggered events
    • Enhanced production of ROS.
      • These free radicals give rise to lipid peroxidation, protein oxidation and DNA damage.
    • Enhanced Lipolysis
      • Calcium activates enzymes, degrading phospholipids to biologically active compounds which are mediators of membrane dysfunction
    • Altered Phosphorylation of Proteins
      • When proteins are phosphorylated and dephosphorylated, their functions are altered.
  • ROS
  • Nitric oxide induced cell damage
    • NO is an innocuous gas produced in:
      • Glial cells
      • Neurons, and also
      • Vascular endothelium (vasorelaxant)
    • NO is an EDRF useful in the blood vessels, but harmful inside brain cells
    • NO produced by the Ca++dependent n-NOS harms as it allows toxic ROS to be formed.
    • Thus, pharmacological manipulation of NO may represent a novel means of protecting the brain from ischaemic nNOS insult.
    Nitric oxide in acute ischaemic stroke, J Neurol Neurosurg Psychiatry 2000;68:123 ( January ) nNOS = neuronal Nitric oxide Synthase
  • Nitric oxide induced cell damage
    • NO, when combined with superoxide:
      • NO + O2- = ONOO-
      • ONOO- is a highly reactive free radical species that produces damage in neurons.
    • Thus, under ischemic conditions, neuronal NOS and i-NOS, which is involved in synaptic signalling mediates cell death.
  • Concept of free radicals
    • Free radicals have one or more unpaired electrons in their outer orbital.
  • Concept of free radicals
    • As a consequence they have an increased reactivity with other molecules.
    • Oxygen centered radicals are the most common type and hence the word - ROS
    • Free radicals produce damage by
      • reacting (oxidizing) with critical cellular elements, usually structural membrane lipids, proteins & DNA; causing lipid peroxidation, protein oxidation and DNA damage.
  • ROS induced cell damage ROS Inactivate & damage critical memb. Proteins like Na + & Ca ++ pumps, creatin kinase, mitochondrial superoxidase Calpain mediated proteolysis Oxidation of Na+ K+ ATPase exchanger Protein side chain oxidation Glycosylic bond cleavage ROS Nucleic acid damage by Chemical modification of nucleic acid base Crosslinking of protein to DNA strand ROS Nucleic acid elongation, altered DNA coding Impaired DNA replication & transcription Cell death Lipid peroxidation (fatty acid oxidation
  • ROS – Steady state
  • ROS – Oxidative state
  • ROS – Oxidative state
  • ROS production theories
  • ROS production theories
  • ROS induced cell injury
  • ROS Actions
    • increase of membrane lipid peroxidation
    • increase of prostaglandin production
    • increase of intracellular free calcium
    • alteration of conductivity of ion channels
    • alteration of enzyme activity
    • alteration of release/action of neurotransmitters
    • reduction of half-life of biologically active substances
    • damage of proteins
    • damage of DNA, genes and protein synthesis
    • damage of carbohydrates
  • Convergence in brain cell damage
    • The overwhelming support from various studies is driven towards the fact that reactive oxygen species (ROS) are generated and play a harmful role during the acute and late stages of cerebral ischemia.
    • Relative to its size, the brain experiences an increased rate of oxidative activity, which creates a significant number of free radicals.
    • The brain and nerve tissue contain relatively low level of antioxidants.
    • Any support towards increasing resilience of the brain tissues must be directed towards countering ROS.
  • ROS action prevention / stoppage
    • The effects of ROS could be prevented or stopped by:
    • reduction of their generation
    • - elimination of undesirable physical & chemical influences
    • - protection of tissues from chronic inflammation
    • - protection of tissues from ischemia
    • their elimination
    • - s ubstitution with antioxidant enzyme s
    • - s ubstitution with non-enzyme antioxidants and scavengers
    • interaction with their effects
    • - protection of cells from intracellular free calcium accumulation
    • and its effects
  • ROS action prevention / stoppage
  • Stroke therapy
  • Neuroprotective agents
    • Calcium Channel blockers
      • Nimodipine
      • Flunarizine
    • Free radical scavengers
      • Ebselen
      • Tiralazad
      • Edaravone
    • Calcium Chelators
      • DP-b99
    • GABA agonists
      • Clomethiazole
    • Glutamate antagonists
      • AMPA antagonists:
      • NMDA antagonists
        • NMDA channel blockers
          • Magnesium, Memantine
          • Remacemide
      • Polyamine site antagonists
        • Eliprodil, Ifenprodil
    • Phosphatidylcholine precursor
      • Citicholine (CDP-choline)
    • Leukocyte adhesion inhibitors
      • Anti-ICAM antibody (Enlimomab)
    • Nitric oxide antagonist
      • Lubeluzole
    • Opioid antagonists
      • Naloxone, Nalmefene
    Mechanism uncertain Piracetam – membrane stabilizer
  • How to treat stroke
    • Reperfusion
      • Carotid endarterectomy
      • tPA
    • Anticoagulation
      • Aspirin
      • Warfarin
      • Unfractionated Heparin
      • Dipyrimidole
    • Neuroprotection
      • Repair the flow
      • Make the tissue more resilient to poor blood flow. [backup for poor plumbing]
    • Therapeutic window Concept:
      • Chances of recovery increases with increased flow.
      • Exact time of critical flow unknown for humans.
  • How to treat stroke
    • The plumbing before stroke onset
      • Carotid endarterectomy provides benefits in patients with symptomatic moderate or severe stenosis.
        • North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998 Nov 12;339(20):1415-25
  • How to treat stroke
    • The plumbing after stroke onset
      • Therapy with intravenous t-PA within 3 hours of the onset of ischemic stroke improved clinical outcome at three months.
        • Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995 Dec 14;333(24):1581-7
  • How to treat stroke
    • The repair of poor plumbing by making the tissue more resilient to poor plumbing:
      • Prevent excitotoxicity
      • Block excitotoxicity
      • Block downstream consequences of excitotoxicity
      • Treat non-excitotoxic mechanisms.
      • Treat white matter
    • Prevent Consequences of Glutamate Receptor Activation:
      • Free radical scavengers
      • Nitric Oxide Synthase antagonists
      • Calpain Inhibitors & Inhibitors of other intracellular enzymes,
      • Calcium buffers
  • Edaravone
  • Edaravone
    • Edaravone is a novel antioxidant that is used in Japan since June 2001 for the treatment of patients in the acute stage of cerebral infarction.
    • Let us look at the various theories and understand why Edaravone has emerged as the ideal support therapy for stroke.
  • Advantages of Edaravone activity
    • Edaravone is the world's first cerebral neuroprotective drug which is remarkably effective at the acute stage of cerebral infarction or embolism in alleviating -
      • adverse neurological symptoms,
      • symptoms of interference with daily living activities &
      • functional disabilities from occurring.
  • Criteria for selection
  • Theories of Edaravone activity
    • With neuroprotective agents the aim is to preserve viable brain cells in the ischemic penumbra
    • Experimental studies have shown that:
      • During cerebral ischemia and reperfusion, free radicals may have a significant role in the development of brain injury.
      • Due to the widespread involvement of free radicals in ischemic damage, free radical trapping is a target.
    MMP activation Mitochondrial disruption Dysregulation of cellular processes DNA oxidative injury Cell membrane injury and leakage Free radicals References 1. Green AR et al. Curr Drug Targets CNS Neurol Disord 2005; 4: 109-118 2. Dirnagl U et al. Trends Neurosci 1999; 22: 391-397 Free radical trapping neuroprotectant Free radicals
  • Theories of Edaravone activity
    • Edaravone scavenges ROS and inhibits pro-inflammatory responses after brain ischemia.
    • In particular, post-ischaemic inflammation, leading to brain edema and infarction due to neuronal damage and endothelial cell death, can be relieved by Edaravone.
    • In addition to these antistroke effects, Edaravone has also been shown to prevent oxidative damage to various extracerebral organs and so, Edaravone is expected to play an integral role in the treatment of many oxidative stress-related diseases.
    The Novel Antioxidant Edaravone: From Bench to Bedside, Cardiovascular Therapeutics, Volume 26 Issue 2, Pages 101 – 114, 28 Jun 2008 by Munenori Tahara et al, Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan
  • Neuroprotection could help limit the damage caused by stroke Reference 1. Fisher M. Cerebrovasc Dis 2004; 17(suppl 1): 1-6 With neuroprotection Ischemic damage minimised Without neuroprotection Permanent ischemic damage
  • Pharmacology of Edaravone
    • Mode Of Action : Cerebral protective agent (free radical scavenger); scavenge free radical, inhibits lipid peroxidation, and protects brain cell, endothelial cells and neurons against oxidative stress.
    • Pharmacokinetics :
      • t1/2 (h) = 0.27
      • Plasma Edaravone concentration seems to disappear without accumulation.
      • Rate of binding of Edaravone to human serum protein and to human serum albumin is 92% and 89%
      • Main metabolites include glucuronic acid complex and sulphate complex.
      • Metabolites are excreted through urine
  • Safety
    • When Edaravone is used in combination with antibiotics such as cefazolin sodium, piperacillin sodium and cefotetan, there is a possibility of exacerbation of renal failure.
    • Edavit must be diluted with physiological saline
    • Do not give along with sugar/high octane/amino acid containing liquids; these may reduce Edavit activity
    • Do not use Edaravone in combination with antiepileptic drugs such as diazepam and phenytoin sodium.
  • Precautions and Contraindications
    • Use with caution in renal/liver failure and cardiac disease and in senile (old) patients
    • Contraindicated in pregnancy, lactation and in children
  • Indications and Doses
    • To relieve neurological symptoms caused by acute cerebral infarction and enhance routine activity ability and alleviate functional disorders.
    • Patients should be IV administered with Edavit injection within 24 hours after onset of the stroke
      • 30 mg Edaravone injection twice a day in combination with physiological saline (30 minutes once).
      • One course of treatment should be less than 14 days
  • Other uses of Edaravone - ALS
    • Amyotrophic lateral sclerosis is a chronic, progressive, almost invariably fatal neurological disease.
    • It is a motor neuron disease with evidence of both anterior horn cell and corticospinal tract involvement and marked by gradual degeneration of the neurons in the central nervous system that control voluntary muscles movement.
    • The disorder causes muscles weakness and atrophy throughout the body and both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles.
  • Other uses - ALS
    • Unable to function, the muscles gradually weaken, waste away i.e atrophied, and have fasciculations because of denervation.
      • The incidence of ALS is 1 to 2.5 cases per 100,000 population and the disease occurs primarily in adult life.
      • The etiology of sporadic ALS remains unknown, although 5 to 10% of cases are familial.
    • The diagnosis of ALS requires the presence of both upper and lower motor neuron findings and progressive motor dysfunction.
      • Several theories regarding the pathogenesis of ALS have emerged including glutamate excitotoxicity, free radical oxidative stress, neurofilament accumulation, and autoimmunity.
  • Other uses
    • A small double-blind study with Edaravone has been performed in 40 patients with ALS in Japan.
    • Patients received either Edaravone 30 mg or placebo per day for 5 days for 4 weeks followed by an open-label study in which patients received the drug once a week for another 2 weeks.
      • The study showed no improvement in ALSFRS-R score or FVC,
      • But in a post-hoc analysis, those who had early ALS (defined as an initial high score on the ALSFRS-R scale) and received the drug had a significantly better ALSFRS-R score and FVC after treatment than those receiving placebo.
  • Other uses - CVS
    • Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, chronic heart failure, diabetes mellitus, or hypertension.
    • Studies now focus on clinical findings and on putative mechanisms underlying the beneficial effects of the antioxidative agent Edaravone on the artherosclerotic process in patients with cardiovascular diseases.
  •