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Pretreatment with Phytochemicals To Reduce Secondary Effects of Traumatic Brain Injury John W. Finley*,† School of Nutrition and Food Science, Louisiana State University, Baton Rouge, Louisiana 70803, United States pathway.2 Gao and Finley summarized the potential benefits of crocin in mediating or delaying the influence of crocin on the progression of Alzheimer’s disease, discussing possible mechanisms of action. Unfortunately, like Alzheimer’s disease, there are no established biomarkers for the later stages of TBI, except autopsy. Ideally, the goal would be a treatment that would help prevent or reduce the secondary or chronic effects of TBI. There have been no clinical trials to test the protective effects of crocin or other plant bioactives in the prevention of secondary effects of TBI.3 TBI leads to brain damage, including excitotoxicity, overproduction of free radicals, inflammation, and apoptosis. Neuroprotective phytochemicals found to be active against one or more of these conditions may act in secondary TBI because they have been shown to slow the progression Alzheimer’s disease. Crocin has exhibited a neuroprotective effect against secondary effects of brain trauma, where it was found to improve neurological function in crocin-treated rats as ecently, traumatic brain injury (TBI) has gained great measured by modified neurological severity scores, which visibility because of injury of children and athletes exhibited significant recovery at 7 and 15 days after the trauma. involved in contact sports. This clearly represents a serious Crocin inhibited neuronal apoptosis that was measured by problem and represents about 10% of TBI overall. In younger TUNEL staining. The results were further confirmed by patients, the major causes of TBI are motor vehicle accidents electron microscopy as well as analysis of B cell lymphoma/ and either assault or self-inflicted injury. In ages over 65, the leukemia-2 (Bcl-2) protein expression. primary cause is falls.1 TBI can be broken into two major The secondary changes after TBI are very complex, and components: The first is the mechanical insult or trauma, which much more research is needed to understand the biochemical is not reversible and resistant to any treatment other than changes occurring during the progression of the conditions and prevention. The secondary injury is the cellular damage, which the role of protective bioactive compounds. The current may or may not be immediately observed until immediately or understanding suggests that that oxidative stress, inflammation, not seen for several days. These secondary changes can and disruption of normal metabolic responses are all involved. continue to develop over years and are exacerbated by repeated Many plant phytochemicals have been studied for treatment of trauma, as observed in professional football players. Many of TBI based on their anti-inflammatory activity as well as other the symptoms result in a continuous progression, resulting in possible mechanisms. Scheff and Ansari have prepared an increased dementia and/or suicidal tendencies. There are many excellent review of the influences of plant phytochemicals on research efforts to identify means to delay or prevent the TBI when administered either pre- and post-trauma.4 progression of these changes. The emphasis here is to consider Wang et al. studied the neuroprotective effects of crocin compounds that may help delay the severity or progression of against TBI in mice.2 Mice were subjected to CCI to induce these secondary effects. TBI. Pretreatment with crocin (20 mg/kg), which was Crocin is a pharmacologically active component of saffron administered 30 min before TBI, demonstrated that crocin (Crocus sativus L.), which has been used as an herbal remedy for was effective in the reduction of TBI-induced secondary various diseases, including neurological problems, for centuries. damage and progression of changes. The protective effects In a recent study using a moderate rodent controlled cortical were demonstrated by the improved neurological severity score impact (CCI) model of TBI in mice, crocin [20 mg/kg, (NSS) and brain edema, decreased microglial activation, intraperitoneal injection (i.p.)] was administered 30 min prior attenuated release of several pro-inflammatory cytokines, and to the injury. Crocin administration significantly decreased the cell apoptosis. neurological motor severity score and brain edema at 24 h postIt would be advantageous if a natural product could help injury. These authors also reported a modest reduction in reduce the long-term effects of TBI when administered either markers of neuroinflammation coupled with a significant decrease in cortical terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The proposed Received: September 9, 2017 mechanism of action was activation of the notch signaling
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© XXXX American Chemical Society
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DOI: 10.1021/acs.jafc.7b04212 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry Table 1. Influence of Various Phytochemicals as Pretreatment for Reducing Markers of TBI product
model
edema
crocin curcumin epigallocatechin gallate (EGCG) naringen
mice rats rats Wistar rat
+
oxidative stress
+
inflammation
+ + + +
lesion volume
modified neural score
+
+ +
TUNEL + + NeuN + +
Morris water maze + +
+
(4) Scheff, S. W.; Ansari, M. A. Natural Compounds as a Therapeutic Intervention Following Traumatic Brain Injury: The Role of Phytochemicals. J. Neuraltrauma 2017, 34, 1491−1510.
prior to or immediately after injury that would help delay or prevent the secondary cascade of metabolic changes observed in TBI. Table 1 represents some selected natural compounds discussed by Scheff and Ansari that have been shown to attenuate the secondary post-trauma effects when given prior to the trauma. Ideally, individuals in sports at risk of TBI could consume a therapeutic dose of natural products to help reduce secondary and tertiary effects of the trauma or multiple traumas.4 Several natural ingredients have been studied for reduction of the secondary effects of TBI. Scheff and Ansari have summarized seven criteria to assess benefits of natural products in mediating effects of TBI. In Table 1, no single product provides positive effects in all seven currently used as measures of post-trauma effects in animal model systems. The table illustrates that pretreatment with selected materials may afford some protection against the secondary effects of TBI. In Table 1, the results from their work are summarized assessing posttrauma effects of the natural products when delivered prior to the TBI.4 On the basis of the currently available literature, a protective effect may be found by testing combinations of natural products for pretreatment, reducing the severity of side effects posttrauma, which, concomitantly, improved biomarkers for the metabolomics of the progression of secondary changes and the mechanism of protection of the natural products. Crocin appears to be an excellent core ingredient to develop a combination product because of the extensive knowledge and clinical data supporting its benefits in delaying the progression of Alzheimer’s disease.
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cellular loss
AUTHOR INFORMATION
Corresponding Author
*E-mail: jfi
[email protected]. ORCID
John W. Finley: 0000-0002-5933-3809 Present Address †
14719 Secret Harbor Place, Lakewood Ranch, Florida 34202, United States. Notes
The author declares no competing financial interest.
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REFERENCES
(1) Centers for Disease Control and Prevention (CDC). Traumatic Brain Injury & Concussion; CDC: Atlanta, GA, 2017; https://www.cdc. gov/traumaticbraininjury/get_the_facts.html (accessed Aug 7, 2017). (2) Wang, K.; Zhang, L.; Rao, W.; Su, N.; Hui, H.; Wang, L.; Peng, C.; Tu, Y.; Zhang, S.; Fei, Z. Neuroprotective Effects of Crocin against Traumatic Brain Injury in Mice: Involvement of Notch Signalling Pathway. Neurosci. Lett. 2015, 591, 53−58. (3) Finley, J. W.; Gao, S. A Perspective on Crocus sativus L. (Saffron) Constituent Crocin: A Potent Water-Soluble Antioxidant and Potential Therapy for Alzheimer’s Disease. J. Agric. Food Chem. 2017, 65, 1005−1020. B
DOI: 10.1021/acs.jafc.7b04212 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
