DOI: 10.1097/CCM.0b013e31823b8b44

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PMID: 22343869

Issn Print: 0090-3493

Publication Date: 2012/03/01


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Is the animal brain the same as the human brain?*

Javed I. Akhtar

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Traumatic brain injury (TBI) is a worldwide major medical problem causing disability, death, and economic burden to the societies. TBI is an extremely complex entity that involves hematoma, contusion, axonal injury, and hypoxemia, leading to neuronal chemical and metabolic changes (1–3). The early primary insult and delayed secondary alterations dictate the eventual neurologic outcome. There are management guidelines developed by the Brain Trauma Foundation without class I evidence supporting any standard therapy (4). The secondary brain injury can be divided into two categories. First, an endogenous secondary injury that evolves in minutes to days after the initial insult. Such processes include excitotoxicity, oxidative stress, neuronal death cascades, blood-brain barrier disruption, inflammation, energy failure, and vasogenic and cellular edema (1, 2). Second, secondary insult in the field, emergency room, or in intensive care unit, for example, hypotension, hypoxemia, hypercarbia, hyperthermia, hyponatremia, and seizure.
A neuroprotective strategy should include both primary and secondary prevention. The primary prevention is the responsibility of the individual, community, law and order enforcement agencies, legislators, and technological innovations. The burden of secondary injury prevention falls on the healthcare systems, medical workforce, and novel therapeutic approaches. A significant body of research has focused on understanding secondary brain injury mechanisms and developing neuroprotective treatments. However, the success has been far from reality. The morbidity and mortality in TBI remains high.
In this issue of Critical Care Medicine, Bitto and colleagues (5) have published their research in which they attempted to study the neuroprotective effects of melanocortin in TBI in a rat model. The authors used a melanocortin analog (Nle4 D-Phe7) α-melanocyte-stimulating hormone at various intervals until the 7th day of injury. A group of animals was also treated with the selective melanocortin MC4-receptor antagonist HS024. The results of the study show decreased concentration of markers of oxidative stress and inflammation, as well as a reduction in axonal damage and neuronal death. Furthermore, the study showed a decreased systemic inflammatory response. A group of animals was tested for sensory-motor orientation and coordinated limb use at day 7 and memory and spatial learning tested at day 23–30 with reported improved outcome.
Melanocortins have a wide distribution in the body and brain, such that they control nervous, behavioral, endocrine, and immune functions (6). Melanocortins have been studied in reversal of shock, prolonged asphyxia, heart ischemia/reperfusion, renal ischemia, spinal cord injuries, neurodegenerative disorders, and diabetic and toxic neuropathies (6). Most of the data come from animal studies and show variable success. Melanocortins have not been studied in TBI models. The authors' effort to study the effects of melanocortins in TBI should be encouraged. The use of MC4-receptor antagonist makes a compelling point in favor of the results. However, it is also worth noting that the melanocortin analog (Nle4 D-Phe7) α-melanocyte-stimulating hormone is an agonist for MC1, MC3, MC4, and MC5 receptors, with special affinity for MC4 and MC5 receptors (6, 7). It is uncertain if the effect of the melanocortin analog (Nle4 D-Phe7) α-melanocyte-stimulating hormone on receptors other than those through MC4 receptors may have an impact on the results of this study. It is satisfying to see histologic and functional testing in this study. Although, the histologic measurements are short term and long-term histologic measurements are missing. The study is also limited by a small sample size, lack of information on hemodynamic stability, brain swelling, electrolyte abnormality, convulsive status, and effects of anesthetic agent.
Numerous monotherapy studies like this study have shown promise in animal models. But the clinical benefits from these studies have not been proven. The current recommendations are to focus on testing combination therapies (8, 9).
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