Brain Injury Articles 2 - Natural

© 2012

Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats

         (Aiguo, Zhe et al. 2010) Download

BACKGROUND: Reactive oxygen species induce neuronal damage, and their role in reducing synaptic plasticity and function is beginning to be understood. Vitamin E is a potent reactive oxygen species scavenger, which has the potential to reduce oxidative damage encountered after traumatic brain injury (TBI). Brain-derived neurotrophic factor (BDNF) can facilitate synaptic function and support learning by modulating the CaMKII system, synapsin I, and cAMP-response element-binding protein (CREB). The elevation of superoxide dismutase (SOD) and Sir2 (silent information regulator 2) play an important role in resistance to oxidative stress. OBJECTIVE: We examined the possibility that vitamin E supplemented in the diet may help counteract the effects of TBI on the molecular substrates underlying synaptic plasticity and cognitive function in the hippocampus. METHODS: Rats were fed a regular diet with or without 500 IU/kg of vitamin E for 4 weeks (n = 6-8 per group) before a mild fluid percussion injury (FPI) was performed. RESULTS: FPI increased protein oxidation as evidenced by elevated levels of protein carbonyls and reduced levels of SOD and Sir2. In addition, FPI resulted in poor performance in the Morris water maze, which was accompanied by reduced levels of BDNF and its downstream effectors on synaptic plasticity, synapsin I, CREB, and CaMKII. Supplementation of vitamin E in the diet counteracted all the observed effects of FPI. CONCLUSIONS: These results suggest that vitamin E dietary supplementation can protect the brain against the effects of mild TBI on synaptic plasticity and cognition, using molecular systems associated with the maintenance of long-term plasticity, such as BDNF and Sir2.


Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

         (Feng, Paul et al. 2006) Download

Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 +/- 3.6% in vehicle pups (n = 28) to 11.9 +/- 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2alpha measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 +/- 7 pg/g in the shams (n = 6), 175 +/- 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 +/- 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

Creatine protects against excitoxicity in an in vitro model of neurodegeneration

         (Genius, Geiger et al. 2012) Download

Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H(2)O(2). In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H(2)O(2)-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.

Prophylaxis with alpha-lipoic acid against lipopolysaccharide-induced brain injury in rats

         (Goraca and Aslanowicz-Antkowiak 2009) Download

INTRODUCTION: Lipopolysaccharide (LPS) stimulates the synthesis and release of reactive oxygen species that play an important role in the pathogenesis of tissue injuries. In this study the effect of early administration of the antioxidant alpha-lipoic acid (alpha-LA) on brain lipid peroxidation, brain hydrogen peroxide (H(2)O(2)) concentration, and brain total sulfhydryl group (-SH group) content was evaluated in rats with endotoxic shock induced by administration of LPS (Escherichia coli 026:B6, 30 mg/kg i.v.) MATERIALS AND METHODS: Rats were treated intravenously with normal saline or alpha-LA (60 mg/kg) 30 min after LPS injection. After 5 h of observation, the animals were killed and their brains were isolated for the measurements. RESULTS: Injection of LPS alone resulted in the development of shock and oxidative stress, the latter indicated by a significant increase in brain concentrations of thiobarbituric acid-reacting substances (TBARS) and H(2)O(2) and a decrease in total brain -SH group content. Administration of alpha-LA after the LPS challenge resulted in an increase in total -SH group content and a decrease in TBARS and H(2)O(2) concentration in the brain tissue compared with the LPS group. CONCLUSION: The results indicate that alpha-LA treatment effectively protected the brain tissue against endotoxin-induced oxidative stress. Administration of LA could be a useful adjunct to clinical application in the management of septic shock.

Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat

         (Hoane, Pierce et al. 2008) Download

Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of traumatic brain injury (TBI). However, research on this compound has been limited to administration regimens starting shortly after injury. This study was conducted to establish the window of opportunity for NAM administration following controlled cortical impact (CCI) injury to the frontal cortex. Groups of rats were assigned to NAM (50 mg/kg), saline (1 ml/kg), or sham conditions and received contusion injuries or sham procedures. Injections of NAM or saline were administered at 15 min, 4 h, or 8 h post-injury, followed by five boosters at 24 h intervals. Following the last injection, blood was taken for serum NAM analysis. Animals were tested on a variety of tasks to assess somatosensory performance (bilateral tactile adhesive removal and vibrissae-forelimb placement) and cognitive performance (reference and working memory) in the Morris water maze. The results of the serum NAM analysis showed that NAM levels were significantly elevated in treated animals. Behavioral analysis on the tactile removal test showed that all NAM-treated groups facilitated recovery of function compared with saline treatment. On the vibrissae-forelimb placing test all NAM-treated groups also were significantly different from the saline-treated group. However, the acquisition of reference memory was only significantly improved in the 15-min and 4-h groups. In the working memory task both the 15-min and 4-h groups also improved working memory compared with saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 h for the sensorimotor tests but only extends to 4 h post-injury in the cognitive tests. These results suggest that a 50 mg/kg treatment regimen starting at the clinically relevant time point of 4 h may result in attenuated injury severity in the human TBI population.

Variation in chronic nicotinamide treatment after traumatic brain injury can alter components of functional recovery independent of histological damage

         (Hoane, Pierce et al. 2008) Download

Previously, we have shown that the window of opportunity for nicotinamide (NAM) therapy (50 mg/kg) following cortical contusion injuries (CCI) extended to 4-8 hrs post-CCI when administered over a six day post-CCI interval. The purpose of the present study was to determine if a more chronic NAM treatment protocol administered following CCI would extend the current window of opportunity for effective treatment onset. Groups of rats received either unilateral CCI's or sham procedures. Initiation of NAM therapy (50 mg/kg, ip) began at either 15-min, 4-hrs, 8-hrs or 24-hrs post-injury. All groups received daily systemic treatments for 12 days post-CCI at 24 hr intervals. Behavioral assessments were conducted for 28 days post injury and included: vibrissae forelimb placing, bilateral tactile adhesive removal, forelimb asymmetry task and locomotor placing testing. Behavioral analysis on both the tactile removal and locomotor placing tests showed that all NAM-treated groups facilitated recovery of function compared to saline treatment. However, on the vibrissae-forelimb placing and forelimb asymmetry tests only the 4-hr and 8-hr NAM-treated groups were significantly different from the saline-treated group. The lesion analysis showed that treatment with NAM out to 8 hrs post-CCI significantly reduced the size of the injury cavity. The window of opportunity for NAM treatment is task-dependent and in some situations can extend to 24 hrs post-CCI. These results suggest that a long term treatment regimen of 50 mg/kg of NAM starting at the clinically relevant time points may prove efficacious in human TBI.


Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

         (Iskandar, Rizk et al. 2010) Download

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats

            (Kalayci, Unal et al. 2011) Download

BACKGROUND: Head trauma is one of the most important clinical issues that not only can be fatal and disabling, requiring long-term treatment and care, but also can cause heavy financial burden. Formation or distribution of free oxygen radicals should be decreased to enable fixing of poor neurological outcomes and to prevent neuronal damage secondary to ischemia after trauma. Coenzyme Q(1)(0) (CoQ(1)(0)), a component of the mitochondrial electron transport chain, is a strong antioxidant that plays a role in membrane stabilization. In this study, the role of CoQ(1)(0) in the treatment of head trauma is researched by analyzing the histopathological and biochemical effects of CoQ(1)(0) administered after experimental traumatic brain injury in rats. A traumatic brain-injury model was created in all rats. Trauma was inflicted on rats by the free fall of an object of 450 g weight from a height of 70 cm on the frontoparietal midline onto a metal disc fixed between the coronal and the lambdoid sutures after a midline incision was carried out. RESULTS: In the biochemical tests, tissue malondialdehyde (MDA) levels were significantly higher in the traumatic brain-injury group compared to the sham group (p < 0.05). Administration of CoQ(1)(0) after trauma was shown to be protective because it significantly lowered the increased MDA levels (p < 0.05). Comparing the superoxide dismutase (SOD) levels of the four groups, trauma + CoQ(1)(0) group had SOD levels ranging between those of sham group and traumatic brain-injury group, and no statistically significant increase was detected. Histopathological results showed a statistically significant difference between the CoQ(1)(0) and the other trauma-subjected groups with reference to vascular congestion, neuronal loss, nuclear pyknosis, nuclear hyperchromasia, cytoplasmic eosinophilia, and axonal edema (p < 0.05). CONCLUSION: Neuronal degenerative findings and the secondary brain damage and ischemia caused by oxidative stress are decreased by CoQ(1)(0) use in rats with traumatic brain injury.

Pyridoxine administration improves behavioral and anatomical outcome after unilateral contusion injury in the rat

         (Kuypers and Hoane 2010) Download

The purpose of this project was to evaluate the preclinical efficacy of pyridoxine, or vitamin B(6). Rats received a 3.0 mm unilateral controlled cortical impact (CCI) injury of the sensorimotor cortex or sham surgery. Treatment with vitamin B(6) (600 or 300 mg/kg IP) or vehicle was administered at 30 min and 24 h post-CCI. Somatosensory dysfunction was evaluated with the vibrissae-forelimb placing and bilateral tactile adhesive removal tests. Sensorimotor dysfunction was evaluated with the locomotor placing and the forelimb asymmetry tests. On the forelimb asymmetry test both treatment groups displayed no asymmetry bias on any of the testing days post-CCI and were statistically no different than the shams. Both vitamin B(6) groups displayed a significant improvement in behavioral performance on the locomotor placing test compared to the vehicle-treated group. Administration of 600 mg/kg also significantly reduced tactile adhesive removal latencies on days 2, 4, 6, and 12 post-CCI. Both treatment groups were improved in their rate of recovery post-CCI on the vibrissae-forelimb placing test, but only the recovery seen in the 600-mg/kg group was significantly improved compared to vehicle. Finally, the 600-mg/kg dose resulted in significant cortical sparing compared to the vehicle-treated group. In general, the effects of vitamin B(6) on recovery of function were dose-dependent, with the 600-mg/kg dose consistently showing greater recovery than the 300-mg/kg dose. More experimental analyses are warranted to evaluate the potential preclinical efficacy and mechanistic action of vitamin B(6).

Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Laboratory investigation

         (Manabe, Okonkwo et al. 2010) Download

OBJECT: Ischemic injury is a potential complication in a variety of surgical procedures and is a particular impediment to the success of surgeries involving highly vulnerable neural tissue. One approach to limiting this form of injury is to enhance metabolic supply to the affected tissue. Trans-sodium crocetinate (TSC) is a carotenoid compound that has been shown to increase tissue oxygenation by facilitating the diffusivity of small molecules, such as oxygen and glucose. The present study examined the ability of TSC to modify oxygenation in ischemic neural tissue and tested the potential neuroprotective effects of TSC in permanent and temporary models of focal cerebral ischemia. METHODS: Adult male rats (330-370 g) were subjected to either permanent or temporary focal ischemia by simultaneous occlusion of both common carotid arteries and the left middle cerebral artery (3-vessel occlusion [3-VO]). Using the permanent ischemia paradigm, TSC was administered intravenously beginning 10 minutes after the onset of ischemia at 1 of 8 dosages, ranging from 0.023 to 4.580 mg/kg. Cerebral infarct volume was measured 24 hours after the onset of ischemia. The effect of TSC on infarct volume was also tested after temporary (2-hour) ischemia using a dosage of 0.092 mg/kg. In other animals undergoing temporary ischemia, tissue oxygenation was monitored in the ischemic penumbra using a Licox probe. RESULTS: Administration of TSC reduced infarct volume in a dose-dependent manner in the permanent ischemia model, achieving statistical significance at dosages ranging from 0.046 to 0.229 mg/kg. The most effective dosage of TSC in the permanent ischemia experiment (0.092 mg/kg) was further tested using a temporary (2-hour) ischemia paradigm. Infarct volume was reduced significantly by TSC in this ischemia-reperfusion model as well. Recordings of oxygen levels in the ischemic penumbra of the temporary ischemia model showed that TSC increased tissue oxygenation during vascular occlusion, but reduced the oxygen overshoot (hyperoxygenation) that occurs upon reperfusion. CONCLUSIONS: The novel carotenoid compound TSC exerts a neuroprotective influence against permanent and temporary ischemic injury when administered soon after the onset of ischemia. The protective mechanism of TSC remains to be confirmed; however, the permissive effect of TSC on the diffusivity of small molecules is a plausible mechanism based on the observed increase in tissue oxygenation in the ischemic penumbra. This represents a form of protection based on "metabolic reflow" that can occur under conditions of partial vascular perfusion. It is particularly noteworthy that TSC could conceivably limit the progression of a wide variety of cellular injury mechanisms by blunting the ischemic challenge to the brain.

Stuck at the bench: Potential natural neuroprotective compounds for concussion

            (Petraglia, Winkler et al. 2011) Download

BACKGROUND: While numerous laboratory studies have searched for neuroprotective treatment approaches to traumatic brain injury, no therapies have successfully translated from the bench to the bedside. Concussion is a unique form of brain injury, in that the current mainstay of treatment focuses on both physical and cognitive rest. Treatments for concussion are lacking. The concept of neuro-prophylactic compounds or supplements is also an intriguing one, especially as we are learning more about the relationship of numerous sub-concussive blows and/or repetitive concussive impacts and the development of chronic neurodegenerative disease. The use of dietary supplements and herbal remedies has become more common place. METHODS: A literature search was conducted with the objective of identifying and reviewing the pre-clinical and clinical studies investigating the neuroprotective properties of a few of the more widely known compounds and supplements. RESULTS: There are an abundance of pre-clinical studies demonstrating the neuroprotective properties of a variety of these compounds and we review some of those here. While there are an increasing number of well-designed studies investigating the therapeutic potential of these nutraceutical preparations, the clinical evidence is still fairly thin. CONCLUSION: There are encouraging results from laboratory studies demonstrating the multi-mechanistic neuroprotective properties of many naturally occurring compounds. Similarly, there are some intriguing clinical observational studies that potentially suggest both acute and chronic neuroprotective effects. Thus, there is a need for future trials exploring the potential therapeutic benefits of these compounds in the treatment of traumatic brain injury, particularly concussion.

The effects of hypertonic saline and nicotinamide on sensorimotor and cognitive function following cortical contusion injury in the rat

         (Quigley, Tan et al. 2009) Download

Hypertonic saline (HTS) is an accepted treatment for traumatic brain injury (TBI). However, the behavioral and cognitive consequences following HTS administration have not thoroughly been examined. Recent preclinical evidence has suggested that nicotinamide (NAM) is beneficial for recovery of function following TBI. The current study compared the behavioral and cognitive consequences of HTS and NAM as competitive therapeutic agents for the treatment of TBI. Following controlled cortical impact (CCI), bolus administrations of NAM (500 mg/kg), 7.5% HTS, or 0.9% saline Vehicle (1.0 mL/kg) were given at 2, 24, and 48 h post-CCI. Behavioral results revealed that animals treated with NAM and HTS showed significant improvements in beam walk and locomotor placing compared to the Vehicle group. The Morris water maze (MWM) retrograde amnesia test was conducted on day 12 post-CCI and showed that all groups had significant retention of memory compared to injured, Vehicle-treated animals. Working memory was also assessed on days 8-20 using the MWM. The NAM and Vehicle groups quickly acquired the task; however, HTS animals showed no acquisition of this task. Histological examinations revealed that the HTS-treated animals lost significantly more cortical tissue than either the NAM or Vehicle-treated animals. HTS-treated animals showed a greater loss of hippocampal tissue compared to the other groups. In general, NAM showed a faster rate of recovery than HTS without this associated tissue loss. The results of this study reiterate the strengths of NAM following injury and show concerns with bolus administrations of HTS due to the differential effects on cognitive performance and apparent tissue loss.

Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study

         (Sakellaris, Nasis et al. 2008) Download

AIM: The complex pathobiology of traumatic brain injury (TBI) offers numerous targets for potential neuroprotective agents. We evaluate the clinical benefit after creatine (Cr) administration in children and adolescents. METHODS: A prospective, randomized, comparative, open- labelled pilot study of the possible neuroprotective effect of Cr was carried out on 39 children and adolescents, aged between 1 and 18 years of age, with TBI. The Cr was administered for 6 months, at a dose of 0.4 g/kg in an oral suspension form every day. For categorical variables, we used the Chi-square test to identify differences between controls and cases. Statistical significance was defined as a p-value <0.05 and not statistically significant if p-value >0.1. RESULTS: The administration of Cr to children and adolescents with TBI improved results in several parameters, including duration of post traumatic amnesia (PTA), duration of intubation, intensive care unit stay. Significant improvement was recorded in the categories of headache (p<0.001), dizziness (p=0.005) and fatigue (p<0.001), aspects in all patients. No side effects were seen due to Cr administration. CONCLUSION: More specific examinations including brain spectroscopy for in vivo evaluation of Cr can be done, in order to draw conclusions for the optimal duration and manner of Cr supply, as well as its possible role for the prevention of TBI complications, in double blind studies.

Neuroprotection by acetyl-L-carnitine after traumatic injury to the immature rat brain

         (Scafidi, Racz et al. 2010) Download

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in children and is characterized by reduced aerobic cerebral energy metabolism early after injury, possibly due to impaired activity of the pyruvate dehydrogenase complex. Exogenous acetyl-L-carnitine (ALCAR) is metabolized in the brain to acetyl coenzyme A and subsequently enters the tricarboxylic acid cycle. ALCAR administration is neuroprotective in animal models of cerebral ischemia and spinal cord injury, but has not been tested for TBI. This study tested the hypothesis that treatment with ALCAR during the first 24 h following TBI in immature rats improves neurologic outcome and reduces cortical lesion volume. Postnatal day 21-22 male rats were isoflurane anesthetized and used in a controlled cortical impact model of TBI to the left parietal cortex. At 1, 4, 12 and 23 h after injury, rats received ALCAR (100 mg/kg, intraperitoneally) or drug vehicle (normal saline). On days 3-7 after surgery, behavior was assessed using beam walking and novel object recognition tests. On day 7, rats were transcardially perfused and brains were harvested for histological assessment of cortical lesion volume, using stereology. Injured animals displayed a significant increase in foot slips compared to sham-operated rats (6 +/- 1 SEM vs. 2 +/- 0.2 on day 3 after trauma; n = 7; p < 0.05). The ALCAR-treated rats were not different from shams and had fewer foot slips compared to vehicle-treated animals (2 +/- 0.4; n = 7; p< 0.05). The frequency of investigating a novel object for saline-treated TBI animals was reduced compared to shams (45 +/- 5% vs. 65 +/- 10%; n = 7; p < 0.05), whereas the frequency of investigation for TBI rats treated with ALCAR was not significantly different from that of shams but significantly higher than that of saline-treated TBI rats (68 +/- 7; p < 0.05). The left parietal cortical lesion volume, expressed as a percentage of the volume of tissue in the right hemisphere, was significantly smaller in ALCAR-treated than in vehicle-treated TBI rats (14 +/- 5% vs. 28 +/- 6%; p < 0.05). We conclude that treatment with ALCAR during the first 24 h after TBI improves behavioral outcomes and reduces brain lesion volume in immature rats within the first 7 days after injury.

N-acetylaspartate as a marker of neuronal injury in neurodegenerative disease

         (Schuff, Meyerhoff et al. 2006) Download


9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein

         (Shen, Luo et al. 2009) Download

Retinoic acid (RA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) or oxygen-glucose deprivation in mesangial and PC12 cells. In cultured human osteosarcoma cells, RA enhances the expression of bone morphogenetic protein-7 (BMP7), a trophic factor that reduces ischemia- or neurotoxin-mediated neurodegeneration in vivo. The purpose of this study is to examine whether RA reduces ischemic brain injury through a BMP7 mechanism. We found that intracerebroventricular administration of 9-cis-retinoic acid (9cRA) enhanced BMP7 mRNA expression, detected by RT-PCR, in rat cerebral cortex at 24 hr after injection. Rats were also subjected to transient focal ischemia induced by ligation of the middle cerebral artery (MCA) at 1 day after 9cRA injection. Pretreatment with 9cRA increased locomotor activity and attenuated neurological deficits 2 days after MCA ligation. 9cRA also reduced cerebral infarction and TUNEL labeling. These protective responses were antagonized by the BMP antagonist noggin given 1 day after 9cRA injection. Taken together, our data suggest that 9cRA has protective effects against ischemia-induced injury, and these effects involve BMPs.

Preclinical efficacy testing in middle-aged rats: nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact

         (Swan, Chandrashekar et al. 2011) Download

Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500 mg/kg or 50 mg/kg) or saline alone (1 mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1 h and 24 h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood-brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50 mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials.

Neural protection by naturopathic compounds-an example of tetramethylpyrazine from retina to brain

            (Tan 2009) Download

Given the advantages of being stable in the ambient environment, being permeable to the blood-brain and/or blood-eye barriers and being convenient for administration, naturopathic compounds have growingly become promising therapeutic candidates for neural protection. Extracted from one of the most common Chinese herbal medicines, tetramethylpyrazine (TMP), also designated as ligustrazine, has been suggested to be neuroprotective in the central nervous system as well as the peripheral nerve network. Although the detailed molecular mechanisms of its efficacy for neural protection are understood limitedly, accumulating evidence suggests that antioxidative stress, antagonism for calcium, and suppression of pro-inflammatory factors contribute significantly to its neuroprotection. In animal studies, systemic administration of TMP (subcutaneous injection, 50 mg/kg) significantly blocked neuronal degeneration in hippocampus as well as the other vulnerable regions in brains of Sprague-Dawley rats following kainate-induced prolonged seizures. Results from us and others also demonstrated potent neuroprotective efficacy of TMP for retinal cells and robust benefits for brain in Alzheimer's disease or other brain injury. These results suggest a promising prospect for TMP to be used as a treatment of specific neurodegenerative diseases. Given the assessment of the distribution, metabolism, excretion, and toxicity information that is already available on most neuroprotective naturopathic compounds such as TMP, it would not take much preclinical data to justify bringing such therapeutic compounds to clinical trials in humans.


References

Aiguo, W., Y. Zhe, et al. (2010). "Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats." Neurorehabil Neural Repair 24(3): 290-8.

Feng, Y., I. A. Paul, et al. (2006). "Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat." Brain Res Bull 69(2): 117-22.

Genius, J., J. Geiger, et al. (2012). "Creatine protects against excitoxicity in an in vitro model of neurodegeneration." PLoS One 7(2): e30554.

Goraca, A. and K. Aslanowicz-Antkowiak (2009). "Prophylaxis with alpha-lipoic acid against lipopolysaccharide-induced brain injury in rats." Arch Immunol Ther Exp (Warsz) 57(2): 141-6.

Hoane, M. R., J. L. Pierce, et al. (2008). "Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat." Neuroscience 154(3): 861-8.

Hoane, M. R., J. L. Pierce, et al. (2008). "Variation in chronic nicotinamide treatment after traumatic brain injury can alter components of functional recovery independent of histological damage." Oxid Med Cell Longev 1(1): 46-53.

Iskandar, B. J., E. Rizk, et al. (2010). "Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation." J Clin Invest 120(5): 1603-16.

Kalayci, M., M. M. Unal, et al. (2011). "Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats." BMC Neurosci 12: 75.

Kuypers, N. J. and M. R. Hoane (2010). "Pyridoxine administration improves behavioral and anatomical outcome after unilateral contusion injury in the rat." J Neurotrauma 27(7): 1275-82.

Manabe, H., D. O. Okonkwo, et al. (2010). "Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Laboratory investigation." J Neurosurg 113(4): 802-9.

Petraglia, A. L., E. A. Winkler, et al. (2011). "Stuck at the bench: Potential natural neuroprotective compounds for concussion." Surg Neurol Int 2: 146.

Quigley, A., A. A. Tan, et al. (2009). "The effects of hypertonic saline and nicotinamide on sensorimotor and cognitive function following cortical contusion injury in the rat." Brain Res 1304: 138-48.

Sakellaris, G., G. Nasis, et al. (2008). "Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study." Acta Paediatr 97(1): 31-4.

Scafidi, S., J. Racz, et al. (2010). "Neuroprotection by acetyl-L-carnitine after traumatic injury to the immature rat brain." Dev Neurosci 32(5-6): 480-7.

Schuff, N., D. J. Meyerhoff, et al. (2006). "N-acetylaspartate as a marker of neuronal injury in neurodegenerative disease." Adv Exp Med Biol 576: 241-62; discussion 361-3.

Shen, H., Y. Luo, et al. (2009). "9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein." J Neurosci Res 87(2): 545-55.

Swan, A. A., R. Chandrashekar, et al. (2011). "Preclinical efficacy testing in middle-aged rats: nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact." J Neurotrauma 28(3): 431-40.

Tan, Z. (2009). "Neural protection by naturopathic compounds-an example of tetramethylpyrazine from retina to brain." J Ocul Biol Dis Infor 2(2): 57-64.