Therapeutic hypothermia: critical review of the molecular mechanisms of action

Abstract

Therapeutic hypothermia (TH) is nowadays one of the most important methods of neuroprotection. The events that occur after an episode of ischemia are multiple and hypothermia can affect the various steps of this cascade. The mechanisms of action of TH are varied and the possible explanation for the benefits of this therapy is probably the multiple mechanisms of action blocking the cascade of ischemia on many levels. TH can affect many metabolic pathways, reactions of inflammation, apoptosis processes, and promote neuronal integrity. To know the mechanisms of action of TH will allow a better understanding about the indications for this therapy and the possibility of searching for other therapies when used in conjunction with hypothermia will provide a therapeutic synergistic effect.

Keywords: cerebral ischemia; excitatory neurotransmitters; mechanism of action; neuronal acidosis; neuronal death; therapeutic hypothermia.

Figure 1

Mechanisms by which therapeutic hypothermia (TH) maintains neuronal integrity after cerebral ischemia. TH blocks the release of excitatory neurotransmitters such as glutamate, aspartate, and dopamine, inhibits the action of glycine in the NMDA receptor, increases angiogenesis, and inhibits ERK pathway by stimulating the formation of BDNF. TH also avoids the transformation and activation of astroglial cells after ischemia. TH, therapeutic hypothermia; NMDA, N-methyl-d-aspartate; BDNF, brain-derived neurotrophic factor.

Figure 2

Mechanisms by which therapeutic hypothermia (TH) avoids apoptosis. TH blocks the TNF pathway and, increases the levels of CIRP; it inhibits the P38, JNK, and ERK pathways. TH avoids apoptosis directly by inhibition of the caspases pathway, blocking caspases 8, 3, 6, 7, 9, and cytochrome C. TH also blocks the P53 protein and affects the Bcl-2 family, blocking pro-apoptotic proteins such as Bax, Bak, Bok, Bid, Delta-PKC, PTEN, AIF, P38, JNK, ERK, granzymes, and reinforcing Epsilon-PKC, Bcl-2, Bcl-XL and Bcl-W, and AKT pathway. TH also avoids degradation of collagen, fibronectin, and proteoglycans by blocking cathepsines. TH, therapeutic hypothermia; TNF, tumor necrosis factor; CIRP, cold-inducible RNA-binding protein; TRADD, TNF receptor-associated death domain; FADD, Fas-associated protein with death domain; ERK, extracellular signal-regulated kinase; JNK, C-Jun-N-terminal protein kinase; AIF: apoptosis inducing factor.

Figure 3

Mechanisms by which therapeutic hypothermia (TH) affects the metabolism and oxidative stress. TH inhibits the formation of lactate, hydrogen, and phosphate, increases glucose reserves and metabolism of the neurons. TH also decreases the levels of TXA2 and prevents vessel occlusion. TH, therapeutic hypothermia; TXA2, thromboxane A2; OH^–, hydroxyl radicals; O₂^–, superoxide; H₂O₂: hydrogen peroxide.