MANHATTAN PROJECT FOR THE BRAIN

Heart tissue starts dying in 40 minutes without blood flow and oxygen, but can be preserved for 6 hours when cooled (as in transplant), whereas the brain starts dying in 3 minutes and fatal in 20 minutes.  Current resuscitation and survival relies on forcing blood flow through the heart, but electric shock and chest compressions can cause damage to a defective heart component.   Cooling may preserve cerebral tissue by reducing metabolism and oxygen demand.  Extrapolating the ratio of heart tissue survival, without and with cooling: 40 minutes – to - 6 hours; cerebral cooling could extend survival from 20 minutes - to – 3 hours and perhaps further.  Task 1, clinical trial for cerebral hypoxia may be broken into separate clinical trials for; heart failure (pandemic disease affecting 29 million), stroke, and hemorrhage.

The hypothesis to be tested: can cooling the head mitigate indications of concussion; slow cerebral bleeding, reduce intracranial swelling, and/or provide better outcomes.  Implications may be; reduction of tau deposits, and effects of chronic traumatic encephalopathy (CTE).

Neurogenic fever is also a primary injury related to heat stroke, a dangerous training hazard that can be fatal. 

 Semin Respir Crit Care Med. 2017 Dec;38(6):768-774. doi: 10.1055/s-0037-1607989. Epub 2017 Dec 20.

Chiu AW1, Hinson HE1.

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Abstract

Traumatic brain injury (TBI) is a serious health care problem on both individual and public health levels. As a major cause of death and disability in the United States, it is associated with a significant economic and public health burden. Although the evidence to support the use of induced hypothermia on neurologic outcome after cardiac arrest is well established, its use in treating TBI remains controversial. Hypothermia has the potential to mitigate some of the destructive processes that occur as part of secondary brain injury after TBI. Hypothermia can be helpful in lowering intracranial pressure, for example, but its influence on functional outcome is unclear. There is insufficient evidence to support the broad use of prophylactic hypothermia for neuroprotection after TBI. Investigators are beginning to more carefully select patients for temperature modulating therapies, in a more personalized approach. Examples include targeting immunomodulation and scaling hypothermia to achieve metabolic targets. This review will summarize the clinical evidence for the use of hypothermia to limit secondary brain injury following acute TBI.

Cryobiology. 2017 Dec 6. pii: S0011-2240(17)30277-8. doi: 10.1016/j.cryobiol.2017.12.004.

Zhou T1, Lin H2, Jiang L1, Yu T1, Zeng C1, Liu J3, Yang Z4.

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1 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

2 Hospital of South China Agricultural University, Guangzhou, China.

3 The Eastern Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: juanhualiu@foxmail.com.

4 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Zengcheng District People's Hospital of Guangzhou, Guangzhou, China. Electronic address: ZhengfeiYVi@163.com.

Abstract

Mild hypothermia (MH) is thought to be one of the most effective therapeutic methods to treat hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA). However, its precise mechanisms remain unclear. In this research, hippocampal neurons were cultured and treated with mild hypothermia and Ac-DEVD-CHO after oxygen-glucose deprivation (OGD). The activity of caspase-3 was detected, in order to find the precise concentration of Ac-DEVD-CHO with the same protective role in OGD injury as MH treatment. Western blot and immunofluorescence staining were conducted to analyze the effects of MH and Ac-DEVD-CHO on the expressions of caspase-3, caspase-8, and PARP. The neuronal morphology was observed with an optical microscope. The lactic acid dehydrogenase (LDH) release rate, neuronal viability, and apoptotic rate were also detected. We found that MH (32 °C) and Ac-DEVD-CHO (5.96 μMol/L) had equal effects on blocking the activation of caspase-3 and the OGD-induced cleavage of PARP, but neither had any effect on the activation of caspase-8, which goes on to activate caspase-3 in the apoptotic pathway. Meanwhile, both MH and Ac-DEVD-CHO had similar effects in protecting cell morphology, reducing LDH release, and inhibiting OGD-induced apoptosis in neurons. They also similarly improved neuronal viability after OGD. In conclusion, caspase-3 serves as a key intervention point of the key modulation site or regulatory region in MH treatment that protects neuronal apoptosis against OGD injury. Inhibiting the expression of caspase-3 had a protective effect against OGD injury in MH treatment, and caspase-3 activation could be applied to evaluate the neuroprotective effectiveness of MH on HIE. 

Patrick M. Kochanek⁎, Travis C. Jackson

a Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, USA

b Safar Center for Resuscitation Research, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA