However, in a model of selective brain cooling (30��C), cortical blood flow measured by laser Doppler flowmetry was shown to increase above control Tenatoprazole? levels [37]. Cerebrovascular changes secondary to cooling the brain are important because reductions in blood flow to critical levels could have adverse effects on tissue survival and functional outcome.Intracellular calcium-dependent signalingThere are pronounced changes in calcium-dependent intra cellular signalling pathways after CNS injury. Normal neuronal activity is mediated by signalling through protein kinases and several of these have been documented to be disrupted by TBI and cerebral ischaemia. Temporary cerebral ischaemia inhibits the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), a key protein kinase that mediates synaptic strength and this is attenuated by hypothermia [38].

Protein kinase C (PKC) translocates to the membrane after cerebral ischaemia and undergoes inhibition; hypothermia rescues the inhibition of PKC activity and its translocation to the membrane [39]. Recently, various transcription factors that participate in normal neuronal functioning have been shown to be sensitive to temperature. The immediate early gene c-Fos, which regulates key genetic responses of neurons, is activated by hypothermia after transient global ischaemia [17,40,41]. These studies underline that temperature may have profound effects on events associated with neuronal injury as well as the normal processing of neuronal signals throughout brain circuits.

Neuronal cell deathAlthough neuronal necrosis is commonly seen in most CNS injury models, evidence for apoptotic cell death has also been documented using various histochemical and molecular techniques. As with necrosis, apoptotic cell death appears Entinostat to be sensitive to post-injury hypothermic treatment strategies. Recent studies indicate that apoptotic cell death is another important target by which temperature may affect long-term outcome in various models of CNS injury. Various gene families (genes with a similar sequence of DNA nucleotides) have been shown to be sensitive to post-injury temperature manipulations in models of ischaemia and trauma [42]. The ability of post-injury temperature to affect the acute and more delayed genetic response to injury is important in that these genes may be important in determining the cellular response or responses that result in secondary injury. Genomic studies using high-throughput screening and bioinformatics are ongoing in many laboratories and these contemporary technologies will help to determine how hypothermia may protect and potentially repair CNS tissues after injury.Systematic review and meta-analysis have not been rigorously applied to TBI models.