Hypothermic neuroprotection

Abstract

Summary:The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment.

Global Birth Hypoxia Increases the Neonatal Testosterone Surge in the Rat

“…This contrasts with effects of hypothermia on hypoxia-induced CNS damage. Hypothermia is well documented to decrease CNS damage due to hypoxia/ischemia and to excitotoxic insult, and to decrease hypoxia-induced glutamate release in the CNS [25]. The finding that the hypoxia-induced increase in testosterone was not blocked by hypothermia is consistent with the idea that central release of glutamate is unlikely to be involved in mediating the increase in testosterone.…”

“…N-Methyl- D -aspartate (NMDA) receptor activation in the hypothalamus is known to stimulate gonadotropin-releasing hormone (GnRH) release leading to secretion of luteinizing hormone (LH) and testosterone in the rat [22], while NMDA receptor blockade also decreases testosterone release prenatally in rats [23]. CNS hypoxia is well known to stimulate acute release of glutamate [24, 25], suggesting the possibility that increased NMDA receptor activation might be responsible for the increased neonatal testosterone levels induced by birth hypoxia. To test this, we assessed effects of NMDA receptor blockade on the hypoxia-induced changes in testosterone, and measured levels of LH and follicle-stimulating hormone (FSH) after birth hypoxia.…”

“…To test this, we assessed effects of NMDA receptor blockade on the hypoxia-induced changes in testosterone, and measured levels of LH and follicle-stimulating hormone (FSH) after birth hypoxia. In addition, we assessed neonatal testosterone following birth hypoxia at a hypothermic temperature, a condition known to decrease hypoxia-induced glutamate release and CNS damage [25]. Adrenocorticotropic hormone (ACTH) and corticosterone are additional circulating hormones known to modulate testicular and adrenal testosterone production [26,27,28,29,30].…”

Pitfalls in the Quest of Neuroprotectants for the Perinatal Brain

“…However, differences between the preclinical model and the clinical situation create a conundrum. For understandable reasons, in animal models, optimized hypothermia leads to a very high level of neuroprotection [14]. How then does one proceed to design an experiment to test add-on therapies?…”

A Head and Neck Support Device for Inducing Local Hypothermia

“…Nevertheless, the exact underlying effects of induced clinical hypothermia as a neuroprotection are still under investigation [8]. Cranial hypothermia may reduce neuronal damage from excitotoxins, apoptosis, and inflammation [13,[15][16][17][18].…”