New Evidence In Mice That Cocaine Makes Brain Cells Cannibalize Themselves

New Evidence in Mice That Cocaine Makes Brain Cells Cannibalize Themselves

Working with mice, researchers at Johns Hopkins have contributed significant new evidence to support the idea that high doses of cocaine kill brain cells by triggering overactive autophagy, a process in which cells literally digest their own insides. Their results, moreover, bring with them a possible antidote, an experimental compound dubbed CGP3466B.

A summary of the study, which also found signs of autophagy in the brain cells of mice whose mothers received cocaine while pregnant, was published online the week of Jan. 18 in the Proceedings of the National Academy of Sciences.

(Image caption: A neural cell from a mouse brain shows much larger, more numerous vacuoles (orange) after 3 hours of treatment with cocaine than untreated cells. Credit: Prasun Guha, Maged Harraz, Solomon Snyder)

(Image caption: An untreated neural cell from a mouse brain shows no vacuoles. Credit: Prasun Guha, Maged Harraz, Solomon Snyder)

“We performed ‘autopsies’ to find out how cells die from high doses of cocaine,” says Solomon Snyder, M.D., professor of neuroscience at the Johns Hopkins University School of Medicine. “That information gave us immediate insight into how we might use a known compound to interfere with that process and prevent the damage.”

After discovering in 1990 that brain cells use the gas nitric oxide to communicate, Snyder and his research team have spent decades studying its impact. In 2013, the team found that nitric oxide is involved in cocaine-induced cell death through its interactions with GAPDH, an enzyme, but didn’t learn how precisely the cells were dying.

To find out, the research team examined nerve cells from mouse brains for clues. Snyder says cells, like whole animals, can die from extreme temperatures, toxins and physical trauma, but can also commit “suicide” in three ways that are chemically programmed and controlled by different proteins.

One such way is autophagy, a normal and much-needed cellular “cleanup process” that rids cells of debris that accumulates in membrane-enclosed vacuoles, or “bags” within the cell. These bags fuse with other bags, enzyme-rich lysosomes, which are filled with acids that degrade the contents of the vacuoles. Only when this process accelerates and spins out of control does it cause cell death, Snyder explains.

By measuring changes in the levels of proteins that control each cell death program and by observing the cells’ physical changes, the team saw clearly that cocaine causes neuronal cell death through out-of-control autophagy. That confirmed previous results from two other groups that found cocaine-induced autophagy in astrocytes and microglia, which are neuron support cells.

“A cell is like a household that is constantly generating trash,” says Prasun Guha, Ph.D., postdoctoral fellow at Johns Hopkins and lead author of the paper. “Autophagy is the housekeeper that takes out the trash — it’s usually a good thing. But cocaine makes the housekeeper throw away really important things, like mitochondria, which produce energy for the cell.”

Because the team already knew that nitric oxide and GAPDH were involved in the process, they tested the ability of the compound CGP3466B, known to disrupt nitric oxide/GAPDH interactions, to halt cocaine-induced autophagy. They also tested other chemicals known to prevent the other two forms of cellular suicide, but only CGP3466B protected mouse nerve cells in the brain from death by cocaine.

According to previous research from the same team, CGP3466B was also able to rescue the brain cells of live mice from the deadly effects of cocaine, but they had not connected the phenomenon to autophagy. When the scientists recently gave mice a single dose of cocaine and looked for signs of autophagy in their brain cells, they detected autophagy-associated proteins and changes in vacuoles in adults and in mouse pups whose mothers had received cocaine while pregnant.

“Since cocaine works exclusively to modulate autophagy versus other cell death programs, there’s a better chance that we can develop new targeted therapeutics to suppress its toxicity,” says Maged M. Harraz, Ph.D., a research associate at Johns Hopkins and lead co-author of the paper.

Snyder says the team hopes its work will eventually lead to treatments that protect adults and infants from the devastating effects of cocaine on the brain. Since CGP3466B has already been tested in phase II clinical trials to (unsuccessfully) treat Parkinson’s disease and ALS, it is known to be safe for humans, but the researchers caution that many more years of studies are needed to definitively show whether it is effective for preventing cocaine damage, first in mice, then in humans. They also want to create and test derivatives of CGP3466B to learn more about cocaine-induced autophagy and see if cocaine is killing any cells outside the brain.

How To Read A Stab Wound

Most emergency departments do not see much penetrating trauma. But it is helpful to be able to learn as much as possible from the appearance of these piercing injuries when you do see them. This post will describe the basics of reading stab wounds.

Important: This information will allow some basic interpretation of wounds. It will not qualify you as a forensics expert by any means. I do not recommend that you document any of this information in the medical record unless you have specific forensic training. You should only write things like “a wound was noted in the midepigastrium that is 2 cm in length.” Your note can and will be used in a court of law, and if you are wrong there can be significant consequences for the plaintiff or the defendant. This information is for your edification only.

1. What is the length of the wound? This does not necessarily correspond to the width of the blade. Skin stretches as it is cut, so the wound will usually retract to a length that is shorter than the full width of the blade.

2. Is the item sharp on one side or both? This can usually be determined by the appearance of the wound. A linear wound with two sharp ends is generally a two sided knife. A wound with one flat end and one sharp end is usually from a one-sided weapon. The picture below shows a knife wound with one sharp side.

3. Is there a hilt mark? This can usually be detected by looking for bruising around the wound. The picture below shows a knife wound with a hilt mark.

4. What is the angle? If both edges are symmetric, the knife went straight in. If one surface has a tangential appearance, then the knife was angled toward that side. You can approximate the direction of entry by looking at the tangential surface of the wound edge. In this example, the blade is angling upward toward the right.

5. How deep did it go? You have no way of knowing unless you have the blood stained blade in your possession. And yes, it is possible for the wound to go deeper than the length of the knife, since the abdominal wall or other soft tissues can be pushed inwards during the stab.

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theperpetualscholar

5 years ago

Nictitating Membrane: A Transparent Or Translucent Third Eyelid Present in Some Animals That Can Be

Nictitating Membrane: a transparent or translucent third eyelid present in some animals that can be drawn across the eye for protection and to moisten it while maintaining vision

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theperpetualscholar

8 years ago

Continuing from last week’s bread-making post, here’s a look at what’s behind the smell of fresh-baked bread! http://wp.me/p4aPLT-1Fe

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theperpetualscholar

6 years ago

The Neuroscience of Serial Murder

Why do serial killers commit heinous acts of murder? The answer may be found in the reward center of our brains, or the Nucleus Accumbens. This is where dopamine is created. When you eat sugar, snort cocaine, snack on chocolate, or have sex, that reward center is triggered and dopamine is released. This chemical conveys the feeling of pleasure, reinforcing those prior indulgences you’ve engaged in. If a serial killer has linked sex with torture, killing, or dismemberment, his brain is sending him a signal, making him feel rewarded for his behavior. It’s the same feeling we may get from eating some chocolate ice cream after a long day or a really good orgasm. A serial killer’s brain reinforces his behavior, telling him that whatever he is doing is good and that he should keep doing it. This may explain why serial killers often do not stop until they are caught.

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theperpetualscholar

6 years ago

Organic Chemistry Masterpost

As a chemistry major, I’ve taken sophomore organic chemistry and advanced organic chemistry. I know it’s a highly popular class, so given the demand, I figured I’d contribute some materials I’ve used that led me to success in those classes.

Google Drive:

I have set up a Google Drive folder containing much of these resources I’ve used to study from, and eventually tutor, the class. They are organized in folders by semester.

Summary Sheets

Practice “Workshop” Problems

Practice Exams

Class Notes

Research Papers

Lab Reports

“The Six Pillars of Organic Chemistry” PDF (written by my professor!)

If I end up finding additional resources, I will add more to the Drive. But that should do you well! You can check the original post for updates here.

Study Tips:

Preparing for Organic Chemistry by @quantumheels

Survivng Orgo Lab w/ Awful Partners by @quantumheels

How I Study for Organic Chemistry by @thekimmydiaries

The 10 Commandments of Organic Chemistry by @theorgounderground

Survival 101 In: Organic Chemistry by @chemistrynerd2020

Helpful References:

Basic Survival Skills by @theorgounderground

Intermediate Survival Skills by @theorgounderground

Advanced Combat Skills by @theorgounderground

Reaction Mechanisms by @theorgounderground

Master Chart of All Reactions by @theorgounderground

Substitution vs. Elimination by @theorgounderground

Mechanism Mindmaps by @sprouht-studiesOrganic Chemistry Functional Groups by @compoundchem

Printables:

Organic Chemistry Study Pack by @quantumheels

Reaction Table & Reaction Chart by @rosallindfranklin

Line Reactions & Mechanisms by @studygene

Best YouTube Channels for Orgo:

Leah4Sci (she was my goddess; check out her website, too!)

Khan Academy Organic Chemistry

Master Organic Chemistry (also check out his website!)

The Organic Chemistry Tutor

Other Recommendations:

Organic Chemistry as a Second Langauge (THE BIBLE)

Klein Textbook >>> McMurry Textbook (IMO; my professor assigned McMurry)

Molecular Visions Molecular Modeling Kit

ChemWiki for Organic Chemistry

Interactive Step-by-Step Mechanism Quizzes

Really, this class is not as hard as people make it out to be. If you put in the work, it’s easy to understand. Practice problems are your friend. If your professor assigns “optional” homework, do it anyway. My professor did a “mechanism a day”, which is something you should absolutely do on your own if your professor doesn’t! At times it might be frustrating, but be patient. Your hard work will pay off!

Good luck!

– Melissa ( @quantumheels )

Study Tips | FAQ in Academia | Printables | YouTube | Instagram

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