1) An injury induces changes in the NMDA receptor subunit ratio in rats, increasing sensitivity to glutamate and lowering the threshold for neuronal activation. This allows calcium channels to remain open longer, increasing calcium influx. 2) After an injury in rats, cerebral blood flow is reduced while damaged cells have an increased ATP demand (hypermetabolism), leading to a "cerebral blood flow-glucose metabolism uncoupling" and a lower threshold for further damage. 3) Giving rats a calcium channel blocker after a brain injury reduced neuronal damage and behavioral deficits, confirming the importance of limiting calcium influx as a therapy to reduce injury symptoms.

1. Summary of key literature providing evidence for the neurometabolic cascade of concussion
by Sarah Murray
Injury induces changes in NMDR receptor in rats
(Osteen et al, 2004)3
Changes to the NR1:NR2 NMDA subunit ratio
were found after injury to 92 rats. Positive
correlations were seen between NS1:NR2 ratio
and level of intracellular calcium accumulation
(p=0.89).
These results suggests that the NDMA receptor is
neuroplastic in response to injury for up to 3 days
post injury, increasing sensitivity to glutamate
and lowering the threshold for neuronal
activation. Calcium channels were found to
remain open longer when they were glutamate
sensitive thereby increasing calcium influx.
This lowered the threshold for second injury
References: 1) Katayama et al. Neurosurgery. 2001 2) Xiao BJ et al. Neurol Med Chir. 2000, 3) Osteen C, Giza C and Hovda D. Neurosci. 2004 4) Lee L et al. Exp Neurol. 2004.
5) Giza C & Hovda D. J Athl Train. 2001.
Uncoupling of cerebral blood flow (CBF) after
injury (Xiao et al, 2000)2
Neuronal activity and CBF are normally
‘coupled’ to meet ATP dependant energy
demands.
CBF is reduced 1hr post injury and may peak at
a 50% reduction by 6-12hrs. This occurs
crucially as damaged cells have an increased
ATP demand (hypermetabolism), leading to a’
‘cerebral blood flow – glucose metabolism
uncoupling. During this time, any further injury
will have a reduced threshold for damage.
Any athlete with a suspected concussion
should be removed from play!
Figure 1: Diagram showing the key components of the neuro-metabolic cascade.
Information used in the diagram was sourced from Giza et al, 2001 (3)
Calcium channel blockers (VGCC’s) offer
neuroprotection to neuronal damage after
concussion (Lee et al, 2004)4
An SNX-185 N-type VGCC blocker was given to rats
15mins after lateral percussion injury. A 60%
reduction in neuronal damage and fewer behavioural
deficits were seen compared to controls when
examined with MRI and a balance beam test.
High cerebral Ca2+ levels may result in apoptosis,
proteolysis and synthesis of reactive oxygen species.
This study therefore confirms the importance of
limiting calcium influx as a therapy to reduce
neuronal damage and limit the symptoms of injury.
Massive efflux of K+ and glutamate after
concussion (Katayama et al, 2010) 1
A 1.40 - 2.15x (mild injury) to 4.28 – 5.90x
(severe injury) increase in K+ concentration
in the rat hippocampus, which was
associated with a proportional increases in
glutamate release.
The increase in K+ is likely to be the result
of excitatory amino acid release
immediately after injury
Diffuse Axonal Injury:
Stretchingof anchored
axon tracts
Increases extracellular K+
concentrationdue toopenedK+
voltage dependant channels. Opening
ofK+ channelsleads to further
glutamate release
Glutamate release binding to
NMDA receptor
Influx of calcium: NMDA
receptors create pore allowing
Ca into the cell
ATP dependant NaK+ pump
activation torestore membrane
gradients
Leads to Hypermetabolism
ENERGY CRISIS
A discrepancybetweencellular glucose
demand and ATP supply. Cells cannot now
respondwell to a 2nd
injuryinsult
High intracellular calcium adversely affects
mitochondrial oxidative metabolism-
decreasingATP supply