Molecular and Cellular Pathways as a Target of Therapeutic Hypothermia: Pharmacological Aspect

Abstract

Induced therapeutic hypothermia is the one of the most effective tools against brain injury and inflammation. Even though its beneficial effects are well known, there are a lot of pitfalls to overcome, since the potential adverse effects of systemic hypothermia are still troublesome. Without the knowledge of the precise mechanisms of hypothermia, it will be difficult to tackle the application of hypothermia in clinical fields. Better understanding of the characteristics and modes of hypothermic actions may further extend the usage of hypothermia by developing novel drugs based on the hypothermic mechanisms or by combining hypothermia with other therapeutic modalities such as neuroprotective drugs. In this review, we describe the potential therapeutic targets for the development of new drugs, with a focus on signal pathways, gene expression, and structural changes of cells. Theapeutic hypothermia has been shown to attenuate neuroinflammation by reducing the production of reactive oxygen species and proinflammatory mediators in the central nervous system. Along with the mechanism-based drug targets, applications of therapeutic hypothermia in combination with drug treatment will also be discussed in this review.

Hypothermic Effect of Acute Citral Treatment during LPS-induced Systemic Inflammation in Obese Mice: Reduction of Serum TNF-α and Leptin Levels

“…We observed that acute citral administration caused a reduction in the hypothalamic IL-6 levels in obese mice, when compared with the control group, possibly associated with hypothermic mechanisms during SI. Citral is probably capable of crossing the blood–brain barrier, possibly due to the hydrophobic nature of the molecule and thus induce a neuroprotective effect during SI in obesity [ 65 , 69 ]. This property of citral could explain its ability to lower serum leptin levels and decrease hypothalamic IL-6 levels during SI.…”

“…To develop citral as an important pharmacological alternative for SI, it is necessary to better elucidate the signaling pathways in different individuals. This monoterpene may possess important clinical applications, possibly associated with nanoparticles that would improve its effectiveness as a drug with effects in hypothermia and neuroprotection [ 69 ].…”

The Profile of MMP-9, MMP-9 mRNA Expression, -1562 C/T Polymorphism and Outcome in High-risk Traumatic Brain Injury: The Effect of Therapeutic Mild Hypothermia

“…The dynamic interaction between transcription factors and signal transduction pathways are a key role of mild hypothermia therapy. 46 , 47 , 48) …”

Protective Effects and Magnetic Resonance Imaging Temperature Mapping of Systemic and Focal Hypothermia in Cerebral Ischemia

“…28 Understanding these mechanisms may facilitate the design of pharmacological alternatives with similar protective efficacy and without side effects. 29 A limitation of this study is that FH application to the surface of the head is not a translational approach because the thickness of the skull would necessitate the use of skin-damaging low temperatures and long treatment periods to achieve the target temperature within the brain. In fact, the beneficial effects of selective brain cooling using a cooling helmet are more evident in infants because of their smaller head size and reduced skull thickness.…”