Update: Curcumin for Traumatic Brain Injury

A study determined whether the neuroprotective role of curcumin in mouse TBI is dependent on the NF-E2-related factor (Nrf2) pathway. The Feeney weight-drop contusion model was used to mimic TBI. Curcumin was administered intraperitoneally 15 min after TBI induction, and brains were collected at 24 h after TBI. The levels of Nrf2 and its downstream genes (Hmox-1, Nqo1, Gclm, and Gclc) were detected by Western blot and qRT-PCR at 24 h after TBI. In addition, edema, oxidative damage, cell apoptosis and inflammatory reactions were evaluated in wild type (WT) and Nrf2-knockout (Nrf2-KO) mice to explore the role of Nrf2 signaling after curcumin treatment. In wild type mice, curcumin treatment resulted in reduced ipsilateral cortex injury, neutrophil infiltration, and microglia activation, improving neuron survival against TBI-induced apoptosis and degeneration. These effects were accompanied by increased expression and nuclear translocation of Nrf2, and enhanced expression of antioxidant enzymes. However, Nrf2 deletion attenuated the neuroprotective effects of curcumin in Nrf2-KO mice after TBI. These findings demonstrated that curcumin effects on TBI are associated with the activation the Nrf2 pathway, providing novel insights into the neuroprotective role of Nrf2 and the potential therapeutic use of curcumin for TBI 1).


The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood.

A study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway 2).


The aim of a study was to investigate the potential neuroprotection of curcumin and the possible role of Nrf2-ARE pathway in the weight-drop model of TBI. The administration of curcumin significantly ameliorated secondary brain injury induced by TBI, such as brain water content, oxidative stress, neurological severity score, and neuronal apoptosis. Curcumin possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of cleaved caspase-3. Moreover, curcumin markedly enhanced the translocation of Nrf2 from the cytoplasm to the nucleus, proved by the results of western blot and immunohistochemistry, subsequently increased the expression of downstream factors such as heme oxygenase 1 (HO1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) and prevented the decline of antioxidant enzyme activities. In conclusion, curcumin could increase the activities of antioxidant enzymes and attenuate brain injury in the model of TBI, possibly via the activation of the Nrf2-ARE pathway 3).


In a study, Huang et al., evaluated the therapeutic potential of curcumin for the treatment of DAI and investigated the mechanisms underlying the protective effects of curcumin against neural cell death and axonal injury after DAI. Rats subjected to a model of DAI by head rotational acceleration were treated with vehicle or curcumin to evaluate the effect of curcumin on neuronal and axonal injury. We observed that curcumin (20 mg/kg intraperitoneal) administered 1 h after DAI induction alleviated the aggregation of p-tau and β-APP in neurons, reduced ER-stress-related cell apoptosis, and ameliorated neurological deficits. Further investigation showed that the protective effect of curcumin in DAI was mediated by the PERK/Nrf2 pathway. Curcumin promoted PERK phosphorylation, and then Nrf2 dissociated from Keap1 and was translocated to the nucleus, which activated ATF4, an important bZIP transcription factor that maintains intracellular homeostasis, but inhibited the CHOP, a hallmark of ER stress and ER-associated programmed cell death. In summary, we demonstrate for the first time that curcumin confers protection against abnormal proteins and neuronal apoptosis after DAI, that the process is mediated by strengthening of the unfolded protein response to overcome ER stress, and that the protective effect of curcumin against DAI is dependent on the activation of Nrf2 4).


Neurological function, brain water content and cytokine levels were tested in TLR4⁻/⁻ mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation.

The protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4⁻/⁻ mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment.

The results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI 5).


The neuroprotective effects of curcumin were evaluated in a weight drop model of cortical contusion trauma in rat. Male Wistar rats (350-400 g, n=9) were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and subjected to head injury. Five days before injury, animals randomly received an i.p. bolus of either curcumin (50 and 100 mg/kg/day, n=9) or vehicle (n=9). Two weeks after the injury and drug treatment, animals were sacrificed and a series of brain sections, stained with hematoxylin and eosin (H&E) were evaluated for quantitative brain lesion volume. Two weeks after the injury, oxidative stress parameter (malondialdehyde) was also measured in the brain. Curcumin (100 mg/kg) significantly reduced the size of brain injury-induced lesions (P<0.05). Neurological examinations (rotarod and inclined-plane tests) were performed on days 1, 3, 7 and 14 post-brain injury. Control injured rats had a significant neurological deficit during 2 weeks (P<0.001). The injury increased brain levels of the malondialdehyde by 35.6% and these increases were attenuated by curcumin (100 mg/kg). Curcumin treatment significantly improved the neurological status evaluated during 2 weeks after brain injury. The study demonstrates the protective efficacy of curcumin in rat traumatic brain injury model 6).


In a study, pre-treatment with curcumin (75, 150 mg/kg) or 30 min post-treatment with 300 mg/kg significantly reduced brain water content and improved neurological outcome following a moderate controlled cortical impact in mice. The protective effect of curcumin was associated with a significant attenuation in the acute pericontusional expression of interleukin-1beta, a pro-inflammatory cytokine, after injury. Curcumin also reversed the induction of aquaporin-4, an astrocytic water channel implicated in the development of cellular edema following head trauma. Notably, curcumin blocked IL-1beta-induced aquaporin-4 expression in cultured astrocytes, an effect mediated, at least in part, by reduced activation of the p50 and p65 subunits of nuclear factor kappaB. Consistent with this notion, curcumin preferentially attenuated phosphorylated p65 immunoreactivity in pericontusional astrocytes and decreased the expression of glial fibrillary acidic protein, a reactive astrocyte marker. As a whole, these data suggest clinically achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma, a finding which warrants further investigation 7).


In a study Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition. The fact that oxidative stress is an intrinsic component of the neurological sequel of TBI and other insults indicates that dietary antioxidant therapy is a realistic approach to promote protective mechanisms in the injured brain 8).

1)

Dong W, Yang B, Wang L, Li B, Guo X, Zhang M, Jiang Z, Fu J, Pi J, Guan D, Zhao R. Curcumin plays neuroprotective roles against traumatic brain injury partly via Nrf2 signaling. Toxicol Appl Pharmacol. 2018 May 1;346:28-36. doi: 10.1016/j.taap.2018.03.020. Epub 2018 Mar 21. PubMed PMID: 29571711.
2)

Wei G, Chen B, Lin Q, Li Y, Luo L, He H, Fu H. Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism. Neuroimmunomodulation. 2018 Apr 18. doi: 10.1159/000487998. [Epub ahead of print] PubMed PMID: 29669346.
3)

Dai W, Wang H, Fang J, Zhu Y, Zhou J, Wang X, Zhou Y, Zhou M. Curcumin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE signaling pathway. Brain Res Bull. 2018 Apr 4. pii: S0361-9230(17)30417-3. doi: 10.1016/j.brainresbull.2018.03.020. [Epub ahead of print] PubMed PMID: 29626606.
4)

Huang T, Zhao J, Guo D, Pang H, Zhao Y, Song J. Curcumin mitigates axonal injury and neuronal cell apoptosis through the PERK/Nrf2 signaling pathway following diffuse axonal injury. Neuroreport. 2018 Mar 22. doi: 10.1097/WNR.0000000000001015. [Epub ahead of print] PubMed PMID: 29570500.
5)

Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK. Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflammation. 2014 Mar 27;11:59. doi: 10.1186/1742-2094-11-59. PubMed PMID: 24669820; PubMed Central PMCID: PMC3986937.
6)

Samini F, Samarghandian S, Borji A, Mohammadi G, bakaian M. Curcumin pretreatment attenuates brain lesion size and improves neurological function following traumatic brain injury in the rat. Pharmacol Biochem Behav. 2013 Sep;110:238-44. doi: 10.1016/j.pbb.2013.07.019. Epub 2013 Aug 7. PubMed PMID: 23932920.
7)

Laird MD, Sukumari-Ramesh S, Swift AE, Meiler SE, Vender JR, Dhandapani KM. Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem. 2010 May;113(3):637-48. doi: 10.1111/j.1471-4159.2010.06630.x. Epub 2010 Jan 20. PubMed PMID: 20132469; PubMed Central PMCID: PMC2911034.
8)

Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol. 2006 Feb;197(2):309-17. Epub 2005 Dec 20. PubMed PMID: 16364299

Update: Prolactinoma Radiosurgery

Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).

GKRS plays a significant role in the treatment of non-functioning [NFA] and hormonal-active [HAA] pituitary adenoma. It affords high rate of tumor control and offers low risk of collateral neurological or endocrine axis injury. A study showed that control of tumor growth was achieved in 90% patients, shrinkage of tumor in 54% and arrest of progression in 36% cases after GKRS treatment. The biochemical remission rate in GH secreting adenoma was 57%, ACTH adenoma was 67% and prolactinoma was 40%. Age less than 50 years and tumor volume less than 5cm3 were associated with a favourable radiosurgical outcome 2).

Case series

2015

Radiotherapy as an alternative and adjuvant treatment for prolactinomas has been performed at the Department of Radiation Oncology, Prince of Wales Cancer Centre, Sydney, New South Wales, Australia, with the linear accelerator since 1990.

In a retrospective review of 13 patients managed with stereotactic radiosurgery (SRS) and 5 managed with fractionated stereotactic radiotherapy (FSRT), as well as 5 managed with conventional radiotherapy, at the Prince of Wales Hospital. Patients with a histopathologically diagnosed prolactinoma were eligible. Those patients who had a confirmed pathological diagnosis of prolactinoma following surgical intervention, a prolactin level elevated above 500 μg/L, or a prolactin level persistently elevated above 200 μg/L with exclusion of other causes were represented in this review.

At the end of documented follow-up (SRS median 6 years, FSRT median 2 years), no SRS patients showed an increase in tumour volume. After FSRT, 1 patient showed an increase in size, 2 showed a decrease in size and 2 patients showed no change. Prolactin levels trended towards improvement after SRS and FSRT, but no patients achieved the remission level of <20 μg/L. Seven of 13 patients in the SRS group achieved a level of <500 μg/L, whereas no patients reached this target after FSRT.

A reduction in prolactin level is frequent after SRS and FSRT for prolactinomas; however, true biochemical remission is uncommon. Tumour volume control in this series was excellent, but this may be related to the natural history of the disease. Morbidity and mortality after stereotactic radiation were very low in this series 3).


Cohen-Inbar et al., reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period.

They reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989-2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up.

Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6-207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission.

GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS 4).

2013

evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm3 (range 0.3–11.6). The marginal tumor dose (median= 15 Gy, range 12–25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12–185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined asa decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six(27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy 5).

2006

Twenty-three patients were included in analysis of endocrine outcomes (median and average follow-up of 55 and 58 mo, respectively) and 28 patients were included in analysis of imaging outcomes (median and average follow-up of 48 and 52 mo, respectively). Twenty-six percent of patients achieved a normal serum prolactin (remission) with an average time of 24.5 months. Remission was significantly associated with being off of a dopamine agonist at the time of GKRS and a tumor volume less than 3.0 cm3 (P < 0.05 for both). Long-term image-based volumetric control was achieved in 89% of patients. Complications included new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two patients (7%).

Clinical remission in 26% of treated patients is a modest result. However, because the GKRS treated tumors were refractory to other therapies and because complication rates were low, GKRS should be part of the armamentarium for treating refractory prolactinomas. Patients with tumors smaller than 3.0 cm3 and who are not receiving dopamine agonist at the time of treatment will likely benefit most 6).

2000

Twenty patients with prolactinomas were followed after GKS. Five patients were treated successfully; their prolactin (PRL) levels dropped into the normal range and dopaminergic drugs could be discontinued. Two spontaneous pregnancies were observed and 11 patients experienced improvement. Improvement was defined as normal PRL levels with the continued possibility of reduced medical treatment or a substantially reduced medical treatment dose with some degree of hyperprolactinemia maintained. The treatment failed in three patients who experienced no improvement. Patients treated with dopaminergic drugs during GKS did significantly less well in comparison with the untreated group when a cumulative distribution function (Kaplan-Meier estimate) was used. CONCLUSIONS:

The results of GKS for prolactinomas in this investigation are better than the results published by others. This may be an effect of case selection because there were no “salvage cases” in our group of patients. Because a dopamine agonist seemed to induce radioprotection in this series, it is suggested that GKS be performed during an intermission in drug therapy when the dopamine agonist is discontinued 7).

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.

2)

Narayan V, Mohammed N, Bir SC, Savardekar AR, Patra DP, Bollam P, Nanda A. Long term Outcome of Non-functioning and Hormonal-active Pituitary Adenoma after Gamma Knife Radio Surgery. World Neurosurg. 2018 Mar 21. pii: S1878-8750(18)30576-X. doi: 10.1016/j.wneu.2018.03.094. [Epub ahead of print] PubMed PMID: 29574220.

3)

Wilson PJ, Williams JR, Smee RI. Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator. J Med Imaging Radiat Oncol. 2015 Jun;59(3):371-8. doi: 10.1111/1754-9485.12257. Epub 2014 Nov 20. PubMed PMID: 25410143.

4)

Cohen-Inbar O, Xu Z, Schlesinger D, Vance ML, Sheehan JP. Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results. Pituitary. 2015 Dec;18(6):820-30. doi: 10.1007/s11102-015-0658-1. PubMed PMID: 25962347.

5)

Liu X, Kano H, Kondziolka D, Park KJ, Iyer A, Shin S, Niranjan A, Flickinger JC, Lunsford LD. Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas. Pituitary. 2013 Mar;16(1):68-75. PubMed PMID: 22302560.

6)

Pouratian N, Sheehan J, Jagannathan J, Laws ER Jr, Steiner L, Vance ML. Gamma knife radiosurgery for medically and surgically refractory prolactinomas. Neurosurgery. 2006 Aug;59(2):255-66; discussion 255-66. PubMed PMID: 16883166.

7)

Landolt AM, Lomax N. Gamma knife radiosurgery for prolactinomas. J Neurosurg. 2000 Dec;93 Suppl 3:14-8. PubMed PMID: 11143231.

Neurotrauma and Critical Care of the Brain

Neurotrauma and Critical Care of the Brain

List Price: $249.99

ADD TO SHOPPING CART

“This book really is a complete primer on the head injured patient. Without a map such as the one this book metaphorically provides, the voyage to mastery can be hazardous for both practitioner and patient.”— Journal of the American Medical Association

Neurotrauma and Critical Care of the Brain, 2nd edition by renowned neurosurgeons Jack Jallo and Christopher Loftus incorporates salient components of the highly praised first edition. The updated text reflects cutting-edge discussion on traumatic brain injury management in a neurocritical care setting. Contributions from top experts in neurosurgery, neurology, critical care, cardiac and pulmonary care, and trauma surgery provide a concise review of a complex and evolving field.

The book lays a solid foundation with discussion of TBI classification, pathophysiology, key blood biomarkers, noninvasive neuromonitoring in severe TBI patients, multimodality monitoring in neurocritical care, and brain imaging modalities. From the prehospital setting to intensive care, top experts share clinical pearls and core guidelines on the management of mild, moderate, and severe TBI and complications. Chapters new to this edition include concomitant injuries, orbital/facial fractures, vascular injuries, spine fractures, autonomic dysfunction, and temperature management.

Key Highlights

  • Specialized topics include wartime penetrating injuries, cardiovascular complications of TBI, venous thromboembolism prophylaxis, ethical considerations, TBI costs in the U.S. and the financial return on helmets
  • Management of pediatric brain injuries in the NICU with illustrative cases
  • Nearly 200 high quality illustrations facilitate understanding of complex anatomy and techniques
  • Summary tables provide a handy overview of injury type, causes, characteristics, and recommended imaging modalities

This remarkable resource is essential reading for neurosurgeons, neurologists, trauma physicians, critical care and rehabilitation medicine specialists, and residents in these specialties. Paired with Neurotrauma and Critical Care of the Spine, 2nd edition, this dynamic duo is the most up-to-date neurocritical care reference available today.