Behavioral Neuro

Stem Cells for Spinal Cord Injuries

neurotopia — Wed, 19 Jul 2006 06:11:12 +0000

Stem Cells for Spinal Cord Injuries

The difficulty with treating spinal cord injuries arises from a number of factors. Firstly there is the primary damage to the axons of the spinal cord itself, resulting in mechanical damage that can inhibit neurotransmission and transport of cellular material to and from the distal cord. The damaged cord must also compensate for secondary damage such as the generation of free radicals, a lack of oxygen to the affected area (anoxia), glial scarring, and a host of other issues.

Your typical spinal neuron looks like this.

(Image snagged from http://www.steve.gb.com). The axon is a long process that extends from the cell body. Axons exit the central nervous system to innervate your muscles, relaying signals from your brain to the muscles and thus telling them when to contract. Your spinal cord is made up of bundles of these axons. Glial cells such as Schwann cells in the periphery or, within the cord itself, oligodendrocytes, wrap themselves around the axon, thus promoting faster transmission of electrical signals and also providing for general maintenance of the environment surrounding the cord, in part by shuttling different compounds around, responding to injury, etc.

Crush injuries to the spinal cord are common, as opposed to clean cuts that sever the cord without any damage to overlying tissue and bone. Crush injuries usually result in low blood flow to the affected area, producing an ischemic condition. Fluid buildup often results, leading to compression from swelling and secondary ischemia. This damage can exceed the amount produced from the primary injury. A whole host of toxic conditions lead to the production of molecules that recruit glial cells to infiltrate the site in an effort to affect repair; unfortunately however, poor design of the system leads to reactive gliosis, which basically means the glial cells are looking to "plug the hole" instead of forming a nice, stable tube to guide the damaged axon back to its target. This glial scarring is an enormous barrier to regeneration of the spinal cord and recovery of function.

Stem cells represent a viable treatment option following spinal cord injury. Undifferentiated stem cells excrete a variety of neurotrophic factors that encourage axon growth, promote the replacement of damaged non-neural structures such as blood vessels, promote the breakdown of the glial scar, and temper inflammatory responses. Embryonic stem cells in particular have a penchant for adopting the glial phenotype, that is they will readily transform into the support cells required by neurons (e.g. astrocytes, oligodendrocytes) once they are transfused into the site of injury. They may also be used to overcome glial repulsion of axons; myelinating cells produce inhibitory factors that can prevent an axon from regenerating.

With that in mind, there are a couple exciting papers coming out. The first I point to uses embryonic stem cells in the rat. These cells, when added to the site of damage along with a PDE-4 inhibitor to block the axon-repulsive effects of glia, were experimentally differentiated into a neural phenotype to form bridge connections between the degenerating axons and the muscle. The interesting manipulation in this paper was the infusion of cells that produce the trophic factor GDNF into the target muscle; GDNF provides a signal that attracts growth of axons from the embryonic stem cells. Here's a crappy MS Paint schematic I made to show what's going on.

Here is an example of a confocal microscopy image of neuromuscular junction formation. The green axons express GFP for labeling purposes, and the red is muscle as labeled by alpha-bungarotoxin. Note the tight association between muscle and axon. Functional recovery was assessed via hind-limb grip strength and mobility, and electrophysiological measures. Significant recovery is shown at 120 days.

A second paper that I won't go into in detail (primarily because it is only available as a PDF and I can't easily dissect out the pretty pictures to show you) expands upon the promise of animal stem cell models of spinal cord injury by using human neural stem cells in a rodent model. They demonstrate differentiation of the human cells into neuronal and glial tissue, axon remyelination, synapse formation, and locomotor recovery. It seems, then, that stem cell therapies hold promise for treatment of traumatic spinal cord injury. While much work remains to develop a stable, consistent model in animals we are definitely making progress, and a variety of very creative approaches are being used. Some of these approaches point directly to potential of human stem cells. A truly pro-life culture would embrace the exploration and use of these technologies for the benefit of all its citizens.

References

Garbossa D, Fontanella M, Fronda C, Benevello C, Muraca G, Ducati A, Vercelli A. Neurol Res. 2006 Jul;28(5):500-4.
Deshpande DM, Kim YS, Martinez T, Carmen J, Dike S, Shats I, Rubin LL, Drummond J, Krishnan C, Hoke A, Maragakis N, Shefner J, Rothstein JD, Kerr DA. Ann Neurol. 2006 Jun 26;60(1):32-44 [Epub ahead of print]
Cummings BJ, Uchida N, Tamaki SJ, Anderson AJ. Neurol Res. 2006 Jul;28(5):474-81.

neurotopia Wed, 07/19/2006 - 02:11

Nobody Expects the Spanish... err, a Chick in an Ape Suit

neurotopia — Mon, 03 Jul 2006 14:13:32 +0000

Nobody Expects the Spanish... err, a Chick in an Ape Suit

Ever wonder how people can be impaired drivers when their blood alcohol content is under the legal limit? This group shows us why. And who can resist an experiment involving a woman in a gorilla suit?

The question the researchers wanted to answer was whether a single drink could impair one's ability to notice something completely out of place. They gave participants a drink in a bar-like setting, then watch a video clip of a basketball game. The oddity was that partway through the clip, a woman in a gorilla suit wanders out to the middle of the screen, beats her chest, and walks off. Totally hot.

Clifasefi and colleagues at Victoria University of Wellington, New Zealand, conducted the pilot study with volunteers between 21 and 35 years old. Half got plain tonic water. But the other half got vodka tonics stiff enough, based on their weight and gender, to raise their blood-alcohol content to 0.04 percent, or half the legal limit for driving in Washington. None of the participants knew for certain what they were getting.

Ok, I have a hard time buying that they couldn't taste the alcohol either. But then again I have a serious conditioned taste aversion to vodka for some strange reason. I think it started around college.

Each participant had 10 minutes to down the drinks. Then they were each shown a video of two three-person teams passing a basketball and asked to count the number of passes.

Among the participants, only four of those who got vodka, or about 18 percent, saw the gorilla. Of the tonic-only crowd, 11, or about 46 percent, spotted the ape.

Now keep in mind this is a tiny study and very preliminary. And I have to question how out-of-place a woman in a gorilla suit is at a basketball game where alcohol is being consumed; maybe drunk people ignore team mascots? Now THAT would be some seriously awesome science!

But, it does suggest that even one drink can result in a phenomenon called inattentional blindness (where out-of-place occurrences go unnoticed). If future studies confirm this finding, it would be worthwhile to determine whether this degree of inattentional blindness is enough to impair driving ability, and whether laws need to be revisited as a consequence.

For fun, you can go here and treat yourself to a few examples of inattentional blindness.

neurotopia Mon, 07/03/2006 - 10:13

PDE-5 Inhibitor Sildenafil Improves Cognition, or Viagra's Good for the Big Head Too

neurotopia — Mon, 26 Jun 2006 21:47:15 +0000

PDE-5 Inhibitor Sildenafil Improves Cognition, or Viagra's Good for the Big Head Too

Inspired by Rush Limbaugh's apparent erectile dysfunction, I decided that today's Evil Journal Club should address the "other" potential uses of PDE-5 inhibitors, the most (in)famous of which is Viagra.

Phosphodiesterase type 5 (PDE-5) is an enzyme that breaks down cyclic GMP. We've known for a while that cGMP is important for signal transduction and ultimately for learning and memory processes, and that nitric oxide (NO) can stimulate production of cGMP. Interestingly, changes in this NO-cGMP signaling pathway have been implicated in aging, providing a potential link to deteriorating cognition with increased age. PDE-5 inhibitors such as sildenafil citrate (Viagra) may therefore act to improve cognition by preventing the enzyme PDE-5 from breaking down cGMP.

The paper in discussion today sought to test this possibility by first demonstrating that memory performance could be impaired by administration of a drug called L-NAME, which blocks NO production by disrupting the activity of the enzyme nitric oxide synthase (NOS). By blocking NOS, L-NAME decreases the amount of NO, which ultimately decreases levels of cGMP and produces cognitive impairment. The primary hypothesis of the paper can then be tested-- does inhibition of PDE-5 prevent learning and memory impairments by ensuring that the remaining cGMP does not get broken down?

The researchers measured memory by use of the 14 unit T maze

Basically, a rat learns to make its way from start to finish, and the number of wrong turns (errors) are recorded. A rat can be tested under the influence of different drugs to determine if the drugs enhance the rate at which the maze is learned (fewer errors over time), memory (fewer errors in later trials but similar numbers of errors while learning), etc.

So the treatments in this study consisted of:

1. Control--- to establish baseline
2. L-NAME-- to demonstrate that NOS inhibition can produce behavioral impairments
3. L-NAME + Sildenafil-- to demonstrate that Sildenafil can prevent behavioral impairments

Four doses of Sildenafil were tested-- 1, 1.5, 3, and 4.5 mg/kg. Multiple doses are used to establish the most effective amount, because pharmacologically we tend to see the proverbial U-shaped curve, where there is an increasing benefit up to a certain dose, then as you continue to go higher performance steadily drops off.

Results are presented as follows: Errors are on the Y axis, and trials are reported on the X axis (trials are grouped together in blocks of three for convenience).

The results:

As you can see, rats that received L-NAME (upside-down triangles) consistently made significantly more errors than the control rats (dark circles) as trials progressed, and it appears that the 1.5 mg/kg dose of Sildenafil (diamonds) could attenuate the effect of L-NAME; their performance is almost equal to that of control animals. If you look at the inset of the figure, you can see the average number of errors across all the blocks of trials. Two asterisks (**) indicate that the L-NAME group performed worse than control, and one asterisk (*) indicates that the 1.5 mg/kg dose of Sildenafil was effective at reversing this impairment.

So in conclusion, Sildenafil can prevent learning impairments produced by inhibiting NOS. While these benefits seem tightly correlated to a narrow dose range of Sildenafil, they join a growing body of literature that suggests PDE-5 inhibitors may provide benefits for the aging individual, beyond those for which they are marketed (to put it politely). These results suggest that the NO-cGMP pathway may be a viable target for drugs that seek to prevent or reverse age-related impairments in learning and memory.

Source: Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition
Psychopharmacology (Berl). 2006 Jan;183(4):439-45. Epub 2005 Nov 18.

neurotopia Mon, 06/26/2006 - 17:47

And when you're in your bigger room...

neurotopia — Fri, 09 Jun 2006 07:34:28 +0000

And when you're in your bigger room...

...you might not know what to do
you might have to think of
how you got started
sittin' in your little room
--The White Stripes

Welcome to the second incarnation of Neurotopia! The old incarnation can be found here, although lately it has just been a collection of posts where I complain about how Blogger stinks. But no more! Now I'm here on this slick new platform! The SEED overlords pulled a mean trick on me: they set up the new blog launch mere hours before I'm supposed to hit the road and celebrate my 8th anniversary by accompanying Mrs. Evil Monkey to Fallingwater for the weekend. Somehow, I will find it in my heart to forgive them.

In the meantime, I'll leave a few links to peruse. If you're new to the field of neuroscience, you can check out the Society for Neuroscience's Brain Facts primer and get acquainted with that lump of jello in your noggin! If you haven't visited this week's Tangled Bank yet, then please do so; some of the best science writing on the net ends up at these bi-weekly festivals! If you're concerned about the state of science education in America, particularly the evolution-creation "controversy", make sure you stop by NCSE for updates. Also, check out Cognitive Daily's Rain Man post.

So once again, welcome! It's great to be here with my fellow Freshman bloggers, and to see some old e-acquaintances. I look forward to tweaking my settings next week when I get back and posting some good science! Might even slap up a picture or two of Frank Lloyd Wright's uber-cool Kaufmann House.

neurotopia Fri, 06/09/2006 - 03:34