BOX 4-1

Physiologic Responses to TBI and Protective/Reparative Targets

Physiologic responses

Intracranial hemorrhage

Release of glutamate/excitotoxicity

Ionic disturbances: Efflux of potassium, influx of calcium and sodium

Decreased cerebral blood flow

Vasogenic edema

Cytotoxic edema

Disruption of the blood-brain barrier

Intravascular coagulation


*Decreased ATP (altered glucose metabolism [hyper- followed by hypoglycolysis] and switch to alternative fuels, elevated lactate) cerebral acidosis

Nonischemic metabolic failure

*Mitochondrial disturbances/failure

Reactive oxygen and nitrogen species




*DNA damage

*Cell injury: apoptosis, necrosis, cytoskeletal changes in cell bodies and processes

Activation of enzymes: e.g., calpains, caspases, endonucleases, metalloproteinases

*Altered neurotransmitters: e.g., catecholamines, serotonin, histamine, acetylcholine, GABA, dopamine

Endogenous Neuroprotective Targets

*Antioxidants (e.g., Cu/Zn-SOD, extracellular SOD, Mn-SOD, glutathione peroxidase, catalase)

Heat shock proteins (e.g., HSP-70, HSP-90, GRP-78, HSP-27)

Hypoxia-inducible-1 factor


Antiapoptotic genes (e.g., XIAP, c-IAP2, Bcl-xL)

Antiapoptotic proteins (e.g., Bcl-2, Bcl-XL)

Growth factors (e.g., bFGF, NGF, BDNF, NT-4, TGF-B, GDNF)

*Anti-inflammatories (e.g., IL-10, IL-18)

Sex hormones (e.g., estrogen, progesterone)

Plasticity/Repair/Recovery Targets

*Neurotrophic factors: (e.g., nerve growth factor, glial-derived neurotrophic factors, neurotrophin 4/5)





*Promising mechanistic target areas for nutritional intervention.

SOURCES: Bales et al., 2009; Bazan, 2006; Bazan et al., 2005; Bramlett and Dietrich, 2004; Dietrich and Bramlett, 2010; Dubreuil et al., 2006; Faden, 2002; Graham et al., 2000; Kokiko and Hamm, 2007; Longhi et al., 2001; Maas et al., 2010; Mammis et al., 2009; Margulies et al., 2009; Marklund et al., 1997, 2006; Mattson et al., 2002; Moppett, 2007; Morales et al., 2005; Morganti-Kossmann et al., 2007; Povlishock and Katz, 2005; Raghupathi, 2004; Royo et al., 2003; Schouten, 2007; Stein et al., 2008; Stetler et al., 2010; Thompson et al., 2005, 2006; Unterberg et al., 2004; Werner and Engelhard, 2007; Yi and Hazell, 2006.

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