Normal
- Mitochondria play an essential role in
- Cerebral energy metabolism,
- Calcium homeostasis,
- Reactive oxygen species generation.
TBI
- Occurs as early as one-hour post TBI
- Mitochondrial dysfunction:
- Is an inability to efficiently carry out oxidative phosphorylation of ADP in the presence of adequate oxygen and metabolic substrate.
- Maintenance of adequate perfusion may not improve clinical outcome due to underlying mitochondrial impairment.
Elevated extracellular glutamate is important in mediating both traumatic and ischaemic brain injury.
- Interstitial glutamate is shown to increase by several mechanisms:
- BBB damage and extravasation of glutamate to region of impact,
- Membrane damage and microporation,
- Upregulation of complexin I and complexin II enhancing exocytosis,
- Glutamate transporter impairment.
- Beta-lactam antibiotics
- (e.g. ceftriaxone)
- Are potent stimulators of glutamate transporter (GLT1)
- Astroglial protein responsible for inactivating synaptic glutamate.
- Beta- lactams increase brain expression of GLT1 and its functional activity → inc. Glutamate breakdown → which decreases glutamate neurotoxicity → neuroprotective potential in ischaemic injury and neuronal degeneration
Pathophysiology
- Glutamate activates NMDA receptors → neuronal depolarization → Excessive Ca2+ influx →
- Calcium- induced mitochondrial matrix swelling → ruptured outer mitochondrial membranes → uncouple the respiratory chain → failure of mitochondrial oxidative phosphorylation → reduction ATP production.
- Failed energy- dependent membrane ion pumps → ion pumps are unable to restore membrane potentials → disruption of neural cellular metabolism homeostasis
- Increases the rate of glycolysis → Inc. lactate production → Lactate accumulation in the CSF and extracellular fluid → acidosis + membrane damage + altered blood brain barrier permeability + cerebral oedema →
- Neuronal dysfunction
- Elevated ICP → Vascular compression → ultimately herniation
- The unregulated influx of calcium and membrane rupturing also induces the opening of the mitochondrial permeability transition pore (mPTP), causing an apoptotic cascade.
- Cyclosporin A
- An immunosuppressant
- Has ability to inhibit mPTP opening in TBI patients
- Demonstrated neuroprotective effects against mitochondrial swelling, membrane breakdown, and ionic homeostatic imbalance (Okonkwo et al., 1999).
- Overactivation of calpains (calcium-activated protease)
- Activation of intracellular digestive enzymes (i.e. peroxidases, proteases, phospholipases) and caspases → structural damage at the subcellular level + DNA degradation + neuronal death (i.e. necrosis and apoptosis).
- Increase production of toxic reactive oxygen species which are key drivers of excitotoxicity after head injury.
- Nitric oxide
- Superoxide
- Hydrogen peroxide
Types of Glutamate receptors
- Ca2+ loading at L- type voltage- sensitive channels is non-toxic,
- Ca2+ loading at NMDA receptors is neurotoxic.
Made with Bullet