ADVERTISEMENT

Pinocembrin: A Natural Compound For Treatment Of Acute Intracerebral Hemorrhage And Traumatic Brain Injury

In the past decades, hospital admissions for acute brain injury have continued to rise. For instance, intracerebral hemorrhage (ICH) and traumatic brain injury (TBI) are just two subtypes of acute brain injury that have increased in annual incidence without a decrease in mortality.

ICH is a type of stroke in which blood accumulates in the brain after a vessel ruptures. When the fluids press against the surrounding tissue, the resulting high pressure leads to mechanical damage within the first minutes to hours. Subsequently, the surrounding brain regions experience secondary damage caused by processes such as loss of blood flow, oxidative stress, and inflammation. Additionally, microglia, brain cells that function in immune defense and as scavengers of dead cells and debris, may further complicate the problem by releasing substances that are toxic to cells. Released chemicals such as nitric oxide, hydrogen peroxide, proteases, cytokines, and acids work together to further damage brain tissue surrounding the lesion but also help eliminate the dead cells at the lesion site.

ADVERTISEMENT

In TBI, the initial blunt trauma to the parenchyma, which is composed of neurons and glial cells, is almost impossible to prevent, and the secondary injury pathways are similar to those of ICH. Consequently, finding viable drugs to ameliorate the effects of secondary injury may be crucial to helping patients recover.

Pinocembrin is one such compound that has shown promise for treating secondary brain injury. It is a natural product found in plants such as ginger root, marjoram, and propolis. Pinocembrin has been found to decrease oxidative stress, inhibit microglial activation, and suppress neuroinflammation. However, pinocembrin’s efficacy and its mechanism of action in ICH and TBI models were unknown. Hence, we investigated its effectiveness for treating ICH and TBI in rat models. The ICH model is created by injecting the enzyme collagenase into the rat’s brain. The enzyme causes blood vessel walls to break down and thus produces bleeding. TBI is induced in rats with a device that drops a piston directly onto the surface of the brain with a pre-set force.

Our novel findings from both studies indicate that pinocembrin has neuroprotective effects against secondary brain injury. It reduced lesion volume and brain fluid accumulation while promoting functional recovery in the ICH model. Similarly, in the TBI model, neuronal survival around the lesion site was greater in animals treated with pinocembrin than in a group that received an inactive compound. Moreover, pinocembrin inhibited activation of microglia and astrocytes. This inhibition, in turn, reduced toxic cytokine production protected the brain.

In the ICH model, CD68, a lysosome marker essential to cell metabolism, and active microglia were observed near the injury site 24 hours after the hemorrhage and were increased significantly at 72 hours. In contrast, the pinocembrin group showed a significantly reduced number of CD68-positive microglia at both time points in comparison to that of the control group. Pinocembrin also suppressed inflammatory signaling proteins, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which are toxic to the brain. Finally, the ICH study suggested that inhibition of the toll-like receptor (TLR) 4 signaling pathway, the major toxic and proinflammatory signaling pathway, might be the major mechanism by which pinocembrin promotes neuroprotection. Six hours after ICH, analysis showed elevated levels of TLR4 and its downstream molecules, MyD88 and TRIF: the two adapters that propagate TLR4 signaling cascades.

ADVERTISEMENT

This finding indicates the presence of a local immune response that may cause secondary brain damage. Additional experiments showed that at 24 hours, application of pinocembrin reduced TLR4 and the expression of associated TLR4 downstream proteins, affirming its neuroprotective property. The neuroprotective effect was not present in microglia-depleted mice or in mice that lacked TLR4. Together, the two studies indicate that pinocembrin improves early outcomes after ICH and TBI through a variety of pathways.

In summary, pinocembrin is a promising drug candidate for treating ICH and TBI. These findings are described in two articles recently published in the journal Brain, Behavior, and Immunity in 2017.1,2 The potential application of pinocembrin to other diseases was described in a review article published in the journal Molecular Neurobiology in 2016. This work was conducted by Drs. Xi Lan, Wenzhu Wang, Jinyuan Zhou, Jian Wang, and others and was supported by grants from the National Institutes of Health, Johns Hopkins University, and the American Heart Association.

References:

  1. Lan X, Han X, Li Qian, Li Qiang, Gao Y, Cheng T, Wan J, Zhu W, Wang J. Pinocembrin protects intracerebral hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia. Brain Behav Immun 2017; 61: 326–339. PMCID: PMC5453178
  2. Wang W, Zhang H, Lee DH, Yu J, Cheng T, Hong M, Jiang S, Fan H, Huang X, Zhou J, Wang J. Using functional and molecular MRI techniques to detect neuroinflammation and neuroprotection after traumatic brain injury. Brain Behav Immun 2017; 64: 344–353. PMCID: PMC5572149
  3. Lan X, Wang W, Li Q, Wang J. The natural flavonoid pinocembrin: molecular targets and potential therapeutic applications. Mol Neurobiol 2016; 53: 1794–1801. PMCID: PMC4561606

Comments

READ THIS NEXT

Capturing The Electrical Activity Of Brain Cells With High Resolution: Novel High-Density Sensors Developed For Neuroscience

Our brain is one of the most complex biological structures known. It contains billions of nerve cells (neurons) which form […]

How Internal Motor Control Structures Afford Sensory Experience

Understanding our social world is a complex task. Indeed, typical environments are noisy, visual information is often degraded, and sometimes […]

Compressed Natural Gas As A Cleaner Solution For Mega-Cities With Mixed Traffic Conditions

Vehicular pollution is considered to be a major source of ambient air pollution in mega-cities of the world like Delhi. […]

3D Green Peanut Hull/Graphene Aerogels For Highly Efficient Oil-Water Separation

Graphene is a very amazing material for its unique gapless conical band structure, its efficient wide range of light absorption, […]

Heterogeneous Mixture Definition

While the term “heterogeneous mixture” sounds like it could be a complicated concept, in reality, it is actually quite simple. […]

5 Homeostasis Examples In Biology

Homeostasis is the tendency for the cells in a body, and therefore the body at large, to maintain a stable […]

Correlated Asteroid Pairs After Encounters With An Unseen Planetary Body Beyond Neptune

When Sedna was discovered in 2003 it was regarded by many as an outlier, nothing else like it was known […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?