Pathophysiology Quiz: Cerebral Perfusion And Ischemia
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Cerebral Perfusion And IschemiaQuestion 1 of 20

The profound lactic acidosis that develops during cerebral ischemia contributes to neuronal injury primarily by which of the following mechanisms?

Causing maximal cerebral vasodilation, which shunts blood away from the penumbra.
Directly activating NMDA receptors in a glutamate-independent manner.
Reversing the action of the Na⁺/Ca²⁺ exchanger, leading to increased intracellular calcium.
Promoting the formation of free radicals through the Fenton reaction and denaturing essential proteins.
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Pathophysiology Quiz: Cerebral Perfusion And Ischemia

Practice Cerebral Perfusion And Ischemia in Pathophysiology with focused quiz questions that help you check what you know, review explanations, and build confidence with test-style prompts.

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This quiz focuses on Cerebral Perfusion And Ischemia, giving you a quick way to practice the rules, question types, and explanations that matter most for Pathophysiology.

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Question 1

The profound lactic acidosis that develops during cerebral ischemia contributes to neuronal injury primarily by which of the following mechanisms?

  1. Causing maximal cerebral vasodilation, which shunts blood away from the penumbra.
  2. Directly activating NMDA receptors in a glutamate-independent manner.
  3. Reversing the action of the Na⁺/Ca²⁺ exchanger, leading to increased intracellular calcium.
  4. Promoting the formation of free radicals through the Fenton reaction and denaturing essential proteins. (correct answer)
Explanation: Low intracellular pH (acidosis) is directly toxic to cells. It can denature structural proteins and enzymes, impairing their function. Furthermore, acidosis facilitates the Fenton reaction, in which iron reacts with hydrogen peroxide to produce highly destructive hydroxyl radicals. This exacerbates oxidative stress and contributes significantly to cell death in the ischemic zone.

Question 2

The anoxic depolarization that occurs in the ischemic core is a pathologically distinct event from a normal physiological action potential. A key feature that distinguishes anoxic depolarization is that it:

  1. is a sustained, terminal depolarization caused by irreversible failure of ion pumps. (correct answer)
  2. is mediated primarily by the efflux of Cl⁻ ions down their concentration gradient.
  3. is a transient, self-limiting event that propagates along the axon.
  4. triggers the release of inhibitory neurotransmitters like GABA to quell excitotoxicity.
Explanation: When you encounter questions about anoxic depolarization versus normal action potentials, focus on the fundamental difference in reversibility and energy dependence. These represent two completely different neuronal events with distinct mechanisms and outcomes. Why A is correct: Anoxic depolarization occurs when ATP depletion causes Na⁺/K⁺-ATPase pumps to fail during ischemia. Without these pumps actively maintaining ionic gradients, sodium floods into the cell while potassium leaks out, creating a sustained depolarization that doesn't repolarize. This is terminal because the cell cannot restore its resting potential without functional energy metabolism—the depolarization persists until cell death occurs. Why the other answers are wrong: Choice B incorrectly identifies chloride efflux as the primary mechanism, when anoxic depolarization is actually driven by sodium influx and potassium efflux due to pump failure. Choice C describes a normal action potential (transient and propagating), which is exactly what anoxic depolarization is NOT—it's sustained and localized to the ischemic tissue. Choice D suggests a protective mechanism involving GABA release, but anoxic depolarization actually promotes excitotoxicity by causing massive calcium influx and glutamate release. Study tip: Remember that anoxic depolarization is fundamentally about energy failure. Normal action potentials depend on maintained gradients and active repolarization, while anoxic depolarization represents the collapse of these gradients when ATP runs out. Think "no energy = no recovery" to distinguish it from reversible neuronal events.

Question 3

Under normal physiological conditions, cerebral blood flow (CBF) is tightly coupled to the cerebral metabolic rate of oxygen (CMRO₂). During a focal epileptic seizure, the affected brain region would be expected to exhibit which of the following changes?

  1. A large increase in CMRO₂ accompanied by a large increase in local CBF. (correct answer)
  2. A large decrease in CMRO₂ with a compensatory increase in local CBF.
  3. A large increase in CMRO₂ but a paradoxical decrease in local CBF.
  4. No significant change in CMRO₂ but a large increase in local CBF.
Explanation: A seizure represents a state of intense, uncontrolled neuronal firing. This hyperactivity demands a massive amount of ATP to maintain ion gradients. Consequently, the cerebral metabolic rate of oxygen (CMRO₂) increases dramatically to support aerobic ATP production. Due to the tight coupling between flow and metabolism, this surge in metabolic demand triggers a corresponding, robust increase in local cerebral blood flow to deliver the necessary oxygen and glucose.

Question 4

A patient in the neuro-intensive care unit has a mean arterial pressure (MAP) of 75 mmHg and an intracranial pressure (ICP) of 30 mmHg. Based on these values, which physiological state is most likely occurring, and what is its primary immediate consequence for neuronal metabolism?

  1. Cerebral perfusion pressure is critically low, leading to a shift toward anaerobic glycolysis and lactate production. (correct answer)
  2. Cerebral autoregulation is maintained, resulting in stable cerebral blood flow and normal aerobic metabolism.
  3. Cerebral perfusion pressure is excessive, causing a breakdown of the blood-brain barrier and vasogenic edema.
  4. Cerebral blood flow is pressure-passive but sufficient, allowing for continued oxidative phosphorylation.
Explanation: Cerebral Perfusion Pressure (CPP) is calculated as MAP - ICP. In this case, CPP = 75 - 30 = 45 mmHg. The lower limit of cerebral autoregulation is typically around 50-60 mmHg. A CPP of 45 mmHg is below this limit, indicating that cerebral blood flow is critically reduced (ischemia). The immediate metabolic consequence of insufficient oxygen delivery is a shift from aerobic respiration to less efficient anaerobic glycolysis, resulting in the production of lactic acid.

Question 5

An experimental neuroprotective agent is found to work by preventing the opening of the mitochondrial permeability transition pore (mPTP) during ischemia and reperfusion. This agent's primary therapeutic benefit would be to prevent:

  1. the collapse of the mitochondrial membrane potential and subsequent release of pro-apoptotic factors. (correct answer)
  2. the initial failure of the Na⁺/K⁺-ATPase pump due to ATP depletion.
  3. the initial excitotoxic release of glutamate from presynaptic terminals.
  4. the inflammatory infiltration of neutrophils across the blood-brain barrier.
Explanation: When you encounter questions about mitochondrial dysfunction in ischemia-reperfusion injury, focus on the sequence of cellular events and what happens when specific protective mechanisms fail. The mitochondrial permeability transition pore (mPTP) normally remains closed to maintain the integrity of the inner mitochondrial membrane. During ischemia-reperfusion, calcium overload and oxidative stress trigger mPTP opening, which creates a large, non-selective channel in the inner mitochondrial membrane. This opening causes immediate collapse of the mitochondrial membrane potential (Δψm\Delta\psi_m) and allows the release of pro-apoptotic factors like cytochrome c and apoptosis-inducing factor from the intermembrane space into the cytosol. These factors then activate caspase cascades leading to apoptotic cell death. An agent preventing mPTP opening would directly block this critical step, making option A correct. Option B is wrong because Na⁺/K⁺-ATPase pump failure occurs early in ischemia due to ATP depletion, before significant mPTP involvement. Option C is incorrect because glutamate excitotoxicity happens during the initial ischemic phase through energy failure and membrane depolarization, not through mPTP mechanisms. Option D is wrong because neutrophil infiltration is primarily an inflammatory response involving cytokines and adhesion molecules, occurring independently of mPTP status. Remember that mPTP opening is specifically a reperfusion injury mechanism that bridges the gap between initial ischemic damage and delayed apoptotic cell death. Questions about neuroprotection often test whether you understand this temporal sequence of injury mechanisms.

Question 6

Nitric oxide (NO) exhibits a dual role in cerebral ischemia. While NO from endothelial NOS (eNOS) can be protective via vasodilation, NO produced in high concentrations by inducible NOS (iNOS) in inflammatory cells is highly neurotoxic. This neurotoxicity is primarily mediated by the reaction of NO with:

  1. glutamate, to form a non-excitotoxic compound.
  2. superoxide radicals, to form the potent oxidant peroxynitrite. (correct answer)
  3. hemoglobin, leading to methemoglobinemia and systemic hypoxia.
  4. calcium, to form precipitates that disrupt cellular function.
Explanation: In the setting of inflammation and oxidative stress that accompanies ischemia/reperfusion, both nitric oxide (NO) and superoxide radicals (O₂⁻) are produced in large quantities. These two radicals react almost instantly to form peroxynitrite (ONOO⁻), a very powerful and destructive oxidant and nitrating agent. Peroxynitrite damages a wide range of biomolecules, including proteins, lipids, and DNA, and is a major mediator of secondary ischemic injury.

Question 7

In the excitotoxicity phase of the ischemic cascade, the massive intracellular influx of calcium (Ca²⁺) through NMDA receptors is a pivotal event. This calcium overload directly triggers which of the following downstream destructive processes?

  1. Hyperpolarization of the neuronal membrane, leading to electrical silence.
  2. Activation of calcium-dependent proteases and lipases that degrade cellular structures. (correct answer)
  3. Upregulation of glutamate transporters to clear the synaptic cleft of excess neurotransmitter.
  4. Direct inhibition of anaerobic glycolysis, halting lactate production.
Explanation: High intracellular calcium concentrations are highly toxic. Calcium overload activates a host of degradative enzymes, including proteases (like calpains) that break down cytoskeletal proteins, phospholipases that degrade cell membranes, and endonucleases that fragment DNA. This enzymatic activity is a major contributor to neuronal death following an ischemic insult.

Question 8

During the initial phase of cerebral ischemia (first 1–2 hours), cytotoxic edema develops rapidly. This form of brain swelling is a direct consequence of which underlying cellular event?

  1. Breakdown of the tight junctions comprising the blood-brain barrier.
  2. Leakage of plasma proteins like albumin into the brain's interstitial space.
  3. Intracellular accumulation of sodium and water secondary to ion pump failure. (correct answer)
  4. Blockage of cerebrospinal fluid reabsorption at the arachnoid granulations.
Explanation: Cytotoxic edema refers to cellular swelling. It is an early event in ischemia caused by the failure of the ATP-dependent Na⁺/K⁺ pump. When the pump fails, sodium is no longer extruded from the cell. The resulting high intracellular sodium concentration creates an osmotic gradient that draws water into the cell, causing it to swell. This is distinct from vasogenic edema, which involves breakdown of the blood-brain barrier and occurs later.

Question 9

A 68-year-old patient presents with symptoms of an acute ischemic stroke. Thrombolytic therapy is administered, and angiography confirms successful recanalization of the occluded middle cerebral artery. Despite the restoration of blood flow, the patient's neurological condition paradoxically worsens over the next 24 hours.

This clinical worsening following the restoration of blood flow is most likely mediated by which key mechanism of reperfusion injury?

  1. Rapid clearance of accumulated lactate, causing a severe intracellular alkalotic shift.
  2. An abrupt resolution of cytotoxic edema, leading to neuronal dehydration and shrinkage.
  3. Massive production of reactive oxygen species (ROS) upon reintroduction of oxygen to ischemic tissue. (correct answer)
  4. Suppression of the local inflammatory response due to washout of pro-inflammatory mediators.
Explanation: Reperfusion injury is a phenomenon where tissue damage is exacerbated after blood flow is restored. A primary mechanism is the massive burst of reactive oxygen species (ROS). During ischemia, the mitochondrial electron transport chain becomes dysfunctional. When oxygen is reintroduced, it is incompletely reduced, generating large amounts of superoxide and other ROS that cause oxidative stress, lipid peroxidation, and further cell damage.

Question 10

An experimental neuroprotective agent is found to work by preventing the opening of the mitochondrial permeability transition pore (mPTP) during ischemia and reperfusion. This agent's primary therapeutic benefit would be to prevent:

  1. the collapse of the mitochondrial membrane potential and subsequent release of pro-apoptotic factors. (correct answer)
  2. the initial failure of the Na⁺/K⁺-ATPase pump due to ATP depletion.
  3. the initial excitotoxic release of glutamate from presynaptic terminals.
  4. the inflammatory infiltration of neutrophils across the blood-brain barrier.
Explanation: When you encounter questions about mitochondrial dysfunction in ischemia-reperfusion injury, focus on the sequence of cellular events and what happens when specific protective mechanisms fail. The mitochondrial permeability transition pore (mPTP) normally remains closed to maintain the integrity of the inner mitochondrial membrane. During ischemia-reperfusion, calcium overload and oxidative stress trigger mPTP opening, which creates a large, non-selective channel in the inner mitochondrial membrane. This opening causes immediate collapse of the mitochondrial membrane potential (Δψm\Delta\psi_m) and allows the release of pro-apoptotic factors like cytochrome c and apoptosis-inducing factor from the intermembrane space into the cytosol. These factors then activate caspase cascades leading to apoptotic cell death. An agent preventing mPTP opening would directly block this critical step, making option A correct. Option B is wrong because Na⁺/K⁺-ATPase pump failure occurs early in ischemia due to ATP depletion, before significant mPTP involvement. Option C is incorrect because glutamate excitotoxicity happens during the initial ischemic phase through energy failure and membrane depolarization, not through mPTP mechanisms. Option D is wrong because neutrophil infiltration is primarily an inflammatory response involving cytokines and adhesion molecules, occurring independently of mPTP status. Remember that mPTP opening is specifically a reperfusion injury mechanism that bridges the gap between initial ischemic damage and delayed apoptotic cell death. Questions about neuroprotection often test whether you understand this temporal sequence of injury mechanisms.

Question 11

A patient with long-standing, poorly controlled hypertension is known to have a right-shifted cerebral autoregulation curve. What is the most significant clinical implication of this physiological adaptation?

  1. The patient's brain is better protected against sudden, severe increases in blood pressure.
  2. The patient is at a significantly higher risk of cerebral ischemia during episodes of relative hypotension. (correct answer)
  3. Cerebral blood flow becomes independent of arterial CO₂ levels, limiting responses to ventilation changes.
  4. The blood-brain barrier is more resilient, reducing the risk of vasogenic edema.
Explanation: A right-shifted autoregulation curve means that the brain maintains constant blood flow at a higher range of mean arterial pressures. The consequence is that the lower limit of autoregulation is also elevated. A blood pressure that would be considered normal or low-normal for a healthy individual (e.g., MAP of 70-80 mmHg) could be below this patient's lower limit, causing a precipitous, pressure-dependent drop in cerebral blood flow and leading to ischemia.

Question 12

Under normal physiological conditions, cerebral blood flow (CBF) is tightly coupled to the cerebral metabolic rate of oxygen (CMRO₂). During a focal epileptic seizure, the affected brain region would be expected to exhibit which of the following changes?

  1. A large increase in CMRO₂ accompanied by a large increase in local CBF. (correct answer)
  2. A large decrease in CMRO₂ with a compensatory increase in local CBF.
  3. A large increase in CMRO₂ but a paradoxical decrease in local CBF.
  4. No significant change in CMRO₂ but a large increase in local CBF.
Explanation: A seizure represents a state of intense, uncontrolled neuronal firing. This hyperactivity demands a massive amount of ATP to maintain ion gradients. Consequently, the cerebral metabolic rate of oxygen (CMRO₂) increases dramatically to support aerobic ATP production. Due to the tight coupling between flow and metabolism, this surge in metabolic demand triggers a corresponding, robust increase in local cerebral blood flow to deliver the necessary oxygen and glucose.

Question 13

The anoxic depolarization that occurs in the ischemic core is a pathologically distinct event from a normal physiological action potential. A key feature that distinguishes anoxic depolarization is that it:

  1. is a sustained, terminal depolarization caused by irreversible failure of ion pumps. (correct answer)
  2. is mediated primarily by the efflux of Cl⁻ ions down their concentration gradient.
  3. is a transient, self-limiting event that propagates along the axon.
  4. triggers the release of inhibitory neurotransmitters like GABA to quell excitotoxicity.
Explanation: When you encounter questions about anoxic depolarization versus normal action potentials, focus on the fundamental difference in reversibility and energy dependence. These represent two completely different neuronal events with distinct mechanisms and outcomes. Why A is correct: Anoxic depolarization occurs when ATP depletion causes Na⁺/K⁺-ATPase pumps to fail during ischemia. Without these pumps actively maintaining ionic gradients, sodium floods into the cell while potassium leaks out, creating a sustained depolarization that doesn't repolarize. This is terminal because the cell cannot restore its resting potential without functional energy metabolism—the depolarization persists until cell death occurs. Why the other answers are wrong: Choice B incorrectly identifies chloride efflux as the primary mechanism, when anoxic depolarization is actually driven by sodium influx and potassium efflux due to pump failure. Choice C describes a normal action potential (transient and propagating), which is exactly what anoxic depolarization is NOT—it's sustained and localized to the ischemic tissue. Choice D suggests a protective mechanism involving GABA release, but anoxic depolarization actually promotes excitotoxicity by causing massive calcium influx and glutamate release. Study tip: Remember that anoxic depolarization is fundamentally about energy failure. Normal action potentials depend on maintained gradients and active repolarization, while anoxic depolarization represents the collapse of these gradients when ATP runs out. Think "no energy = no recovery" to distinguish it from reversible neuronal events.

Question 14

Nitric oxide (NO) exhibits a dual role in cerebral ischemia. While NO from endothelial NOS (eNOS) can be protective via vasodilation, NO produced in high concentrations by inducible NOS (iNOS) in inflammatory cells is highly neurotoxic. This neurotoxicity is primarily mediated by the reaction of NO with:

  1. glutamate, to form a non-excitotoxic compound.
  2. superoxide radicals, to form the potent oxidant peroxynitrite. (correct answer)
  3. hemoglobin, leading to methemoglobinemia and systemic hypoxia.
  4. calcium, to form precipitates that disrupt cellular function.
Explanation: In the setting of inflammation and oxidative stress that accompanies ischemia/reperfusion, both nitric oxide (NO) and superoxide radicals (O₂⁻) are produced in large quantities. These two radicals react almost instantly to form peroxynitrite (ONOO⁻), a very powerful and destructive oxidant and nitrating agent. Peroxynitrite damages a wide range of biomolecules, including proteins, lipids, and DNA, and is a major mediator of secondary ischemic injury.

Question 15

In the excitotoxicity phase of the ischemic cascade, the massive intracellular influx of calcium (Ca²⁺) through NMDA receptors is a pivotal event. This calcium overload directly triggers which of the following downstream destructive processes?

  1. Hyperpolarization of the neuronal membrane, leading to electrical silence.
  2. Activation of calcium-dependent proteases and lipases that degrade cellular structures. (correct answer)
  3. Upregulation of glutamate transporters to clear the synaptic cleft of excess neurotransmitter.
  4. Direct inhibition of anaerobic glycolysis, halting lactate production.
Explanation: High intracellular calcium concentrations are highly toxic. Calcium overload activates a host of degradative enzymes, including proteases (like calpains) that break down cytoskeletal proteins, phospholipases that degrade cell membranes, and endonucleases that fragment DNA. This enzymatic activity is a major contributor to neuronal death following an ischemic insult.

Question 16

A patient with a traumatic brain injury and elevated intracranial pressure (ICP) is mechanically ventilated. To acutely manage the ICP, the ventilation rate is increased to induce a state of moderate hypocapnia (PaCO₂ of 30 mmHg). What is the primary physiological mechanism by which this intervention reduces ICP, and what is the most significant associated risk?

  1. It causes cerebral vasodilation, increasing oxygen delivery to ischemic tissues but risks worsening vasogenic edema.
  2. It decreases the cerebral metabolic rate of oxygen (CMRO₂), reducing metabolic byproducts and lowering parenchymal volume.
  3. It induces cerebral vasoconstriction, reducing cerebral blood volume, but carries a significant risk of causing or worsening cerebral ischemia. (correct answer)
  4. It promotes the transport of cerebrospinal fluid (CSF) into the dural venous sinuses, but risks causing systemic dehydration.
Explanation: Hypocapnia (low arterial CO₂) is a potent cerebral vasoconstrictor. This constriction reduces the volume of blood within the cranial vault, thereby lowering intracranial pressure. However, this vasoconstriction also reduces cerebral blood flow (CBF), which can be detrimental if the patient's cerebral perfusion is already compromised, potentially inducing or exacerbating ischemia.

Question 17

A patient with a severe closed head injury has a mean arterial pressure (MAP) of 90 mmHg and an intracranial pressure (ICP) of 35 mmHg. The clinical team administers a bolus of hypertonic saline.

Assuming the hypertonic saline is effective, what is the intended immediate sequence of physiological changes to improve cerebral perfusion?

  1. Increased MAP → Increased CPP → Decreased ICP
  2. Decreased cerebral edema → Decreased ICP → Increased CPP (correct answer)
  3. Systemic vasodilation → Decreased MAP → Decreased CBF
  4. Decreased CSF production → Decreased ICP → Decreased CBF
Explanation: First, calculate the initial CPP: 90 - 35 = 55 mmHg, which is on the verge of inadequacy. Hypertonic saline is an osmotic agent. It increases serum osmolality, drawing water out of the brain parenchyma across the blood-brain barrier. This reduces cerebral edema and brain volume, which in turn leads to a decrease in ICP. According to the formula CPP = MAP - ICP, a decrease in ICP (with a stable MAP) will result in an increase in CPP, thereby improving cerebral blood flow.

Question 18

A patient in the neuro-intensive care unit has a mean arterial pressure (MAP) of 75 mmHg and an intracranial pressure (ICP) of 30 mmHg. Based on these values, which physiological state is most likely occurring, and what is its primary immediate consequence for neuronal metabolism?

  1. Cerebral perfusion pressure is critically low, leading to a shift toward anaerobic glycolysis and lactate production. (correct answer)
  2. Cerebral autoregulation is maintained, resulting in stable cerebral blood flow and normal aerobic metabolism.
  3. Cerebral perfusion pressure is excessive, causing a breakdown of the blood-brain barrier and vasogenic edema.
  4. Cerebral blood flow is pressure-passive but sufficient, allowing for continued oxidative phosphorylation.
Explanation: Cerebral Perfusion Pressure (CPP) is calculated as MAP - ICP. In this case, CPP = 75 - 30 = 45 mmHg. The lower limit of cerebral autoregulation is typically around 50-60 mmHg. A CPP of 45 mmHg is below this limit, indicating that cerebral blood flow is critically reduced (ischemia). The immediate metabolic consequence of insufficient oxygen delivery is a shift from aerobic respiration to less efficient anaerobic glycolysis, resulting in the production of lactic acid.

Question 19

Apoptosis, or programmed cell death, is a key mechanism of delayed neuronal loss in the ischemic penumbra. The intrinsic apoptotic pathway is most directly initiated by which of the following events?

  1. The initial massive influx of Na⁺, causing acute cellular lysis.
  2. Phagocytosis of stunned but viable neurons by activated microglia.
  3. Release of cytochrome c from the mitochondrial intermembrane space into the cytosol. (correct answer)
  4. The binding of Fas ligand expressed on immune cells to Fas receptors on neurons.
Explanation: The intrinsic pathway of apoptosis is mitochondrial-dependent. Cellular stress, including calcium overload and oxidative stress common in the penumbra, leads to increased permeability of the outer mitochondrial membrane. This allows for the release of pro-apoptotic factors, most notably cytochrome c, into the cytoplasm. Cytosolic cytochrome c then binds with Apaf-1 to form the apoptosome, which activates caspase-9 and initiates the caspase executioner cascade.

Question 20

Following the initial excitotoxic and metabolic insults in cerebral ischemia, a secondary inflammatory response contributes to ongoing tissue damage. Which of the following represents a key mechanism by which this neuroinflammation exacerbates neuronal injury?

  1. Astrocytes rapidly form a glial scar that isolates the ischemic core, preventing nutrient delivery to the penumbra.
  2. Activated microglia and infiltrating leukocytes release cytotoxic mediators, including proteases and reactive oxygen species. (correct answer)
  3. Oligodendrocytes in the penumbra are stimulated to remyelinate damaged axons, leading to excitotoxicity from metabolic overload.
  4. The complement cascade is activated to selectively clear glutamate from synapses, causing neuronal starvation.
Explanation: The inflammatory response in the ischemic brain involves the activation of resident microglia and the infiltration of peripheral immune cells like neutrophils. These cells release a variety of substances intended to clear debris but which also cause collateral damage to surrounding, salvageable tissue. These include pro-inflammatory cytokines (e.g., TNF-α, IL-1β), reactive oxygen species, nitric oxide, and matrix metalloproteinases that degrade the extracellular matrix and blood-brain barrier.