Autoregulation of Cerebra Blood Flow (CBF) is determined by arterial pressure
ischemia disrupts autoregulation: immediately after ischemia, there is hyper- then hypo- perfusion
Definition of Ischemia
: A decrease in CBF sufficient to cause functional or metabolic deficits
Borderline Ischemia
: is a drop in CBF to less than 50% of the control (normal for that person)
these cells will be silent but will resume normal function upon return of normal CBF
this area of ischemia, which is maintained by collateral blood flow, is known as the penumbra; it can be restored after an ischemic attack
Severe Ischemia:
is a drop in CBF to below 20% of normal
triggers events (See below) that jeopardize cell survival even if ischemia only happens for 4-6 minutes
this area of ischemia is known as the ischemic core
infarction of vessel leading to tissue damage occurs when blood flow is reduced by 50%
Energy Metabolism to the Brain
Ischemia is a major threat to the brain by reducing O2 delivery = CBF X CaO2 ; CaO2 = PaO2 X Hb % Saturation
so, reducing CBF, PaO2 or Hb will reduce the O2 supply
brain utilizes 20% of O2 consumption; of which, 45% is used to maintain cell integrity and 55% for neural function
glucose is substrate for brain’s high energy demand; supply is not rate limiting (membrane transport is)
adequacy of the glucose supply is more related to metabolic requirements than CBF
Note: Ischemia is more detrimental than hypoxia alone
(low PaO2 in presence of normal CBF).
the reason is that CBF is required to remove reactive metabolites like NO and ROS (reactive Oxygen species)
also PMNs are able to adhere more easily
Þ inflammatory response Þ cell damage
Bioenergetic Failure
: Consumes ATP and sequentially leads to high levels of Creatinine, ADP then AMP
AMP deaminates resulting in accumulation of nucleotides at the expense of ATP
Ischemic threshold
is point at which ATP will start to be consumed and lactate accumulates. ~ 50% of CBF
Mechanism of Ischemia
Threshold at the penumbra
:
Electrical Threshold
occurs when CBF falls below 30%. Neurons are electrically silent = shut down of Na/K ATPase.
Threshold at the ischemic core
:
Membrane Failure Threshold
occurs < 20% of normal CBF resulting in abnormalities associated with cell death
Glutamate (Glu) Threshold
is at 30% CBF, below which massive amounts of Glu are accumulated at synapse
Glu is an important excitatory neuro transmitter (NT) stored in presynaptic vesicles
when released in to post synaptic cleft Þ binds post synaptic membrane ion transporters (i.e. AMPA receptor triggers Na+/K+ flux which activates NMDA receptor allowing Na+/K+ and Ca++ flux) Þ causes entry of Ca++ into cell via voltage sensitive L and T type Ca channels
Glu binding is self-limiting under normal CBF due to diffusion from cleft and re-uptake by pre-synaptic membrane
total glutamate release is dependent on the duration of ischemia and severity of insult
however, Glu release plateaus during irreversible ischemia, so it is the magnification of the primary response to Glu by the 2nd messengers (primarily triggered by Ca++) that ends up killing the cell
this process occurs in all parts of brain and in all the animal models studied
Hypothermia
(when cold Þ less GLU released) attenuates Glu release, but there are bad side effects (altered liver metabolism, cardiac arrhythmia)
How does Ca++ kill the cell?
– it generates 2nd messengers
Ca++ causes production and induction of NO (3 types Endothelial, Neuronal and Inducible – via NO synthase)
Ca++ release from endoplasmic reticulum (further amplifying effects of Ca++)
enzyme production causes Ý lipid peroxidation, ß protein synthesis with apoptosis, O2 free radicals
mediated by:
Ý
cAMP Þ Ý protein phosphorylation
Ý
IP3 ÞÝ DAG Þ Arachadonic AcidÞ thromboxane etc
normally the above oxidants are counteracted by antioxidants, hemoglobin, Vit C, Vit E, glutathione, catalases
during ischemia, the oxidants overwhelm the antioxidants thus producing cell damage
Physiological Effects of NO
Positives
: enhances regional CBF, inhibits platelet aggregation, platelet and neutraphil adhesion NMDA current
Negatives
: Direct cytotoxicity, produces hydroxyl radicals and peroxi-nitrites, binding to iron-sulfur complexes, inhibition of mitochondrial cytochrome enzymes, DNA deamination, nitrosylation of thiols.
Induction of NO causes negative effects which predominate over the positive effects