John - thanks for your well reasoned response.
As I noted in my original post, I'm not up to date on the biology of NIL-A, but your response invokes recollections of nerve growth factor (NGF) and the problems associated with its use in Alzheimer's Disease (AD). To maintain brevity (!), I'll just cut to the chase: NGF was an ideal and highly specific trophic factor for the neurons which degenerate in AD. One of the primary reasons it is not in use is that it did indeed lead to 'ectopic' sprouting of axon collaterals in experimental animals (ectopic = unwanted sprouting in intact brain regions). Some of the earliest experiments by Victor Hamburger with NGF showed a dorsal root ganglion cell (in vitro) putting out a collateral arborization probably 5000 times its normal density following NGF treatment. Similar, though somewhat less drastic, effects can be produced by NGF in vivo.
When you say, ' Collateral sprouting is going on all of the time in the CNS...(but) since virtually all the space available for a synapse to attach to other neurons is occupied, these collaterals are never able to connect to a receiving cell. These two concepts, ongoing collateral sprouting in the intact adult brain and 'space' constraints as the limiting factor to support new collaterals, are new to me. This may reflect my lapsed training since graduate school...but the fact that NGF did indeed induce new collaterals in a supposedly space constrained adult brain suggests the possibility, at a minimum, exists for NIL-A. Collateral growth may be enhanced by the reduction in the number of synapses at a target site; this does not in any way imply such growth is dependent upon target site availability when enhanced levels of a trophic factor become available. Thus you may be framing this scenario inappropriately: Guilford proposes adding supra-physiological levels of a trophic agent to the brain - under these conditions one must take seriously the idea that all the normal rules for sprouting are history and collaterals may arise in many parts of the brain with abandon.
I would like to see a detailed anatomical study of the brains of the NIL-A treated animals. Since the molecule's trophic activity is completely non-specific, I would be quite surprised if no ectopic sprouting was observed.
There's also another conceptual point that needs to be clarified - those not in the field often assume that if a neuron is driven to produce new 'branches', its survival is likely to be significantly enhanced compared to those neurons not exposed to such trophic treatment. But this may not be the case at all: collateral growth may occur in neurons still able to respond. However, NIL-A does nothing to the underlying disease process in PD. Thus an assumption that NIL-A protects against a nigral dopaminergic neuron falling victim to the disease is highly suspect. A surviving neuron may sprout collaterals in response to NIL-A and thus *may* help replace activity in the nigra. But this same neuron may soon degenerate like its kin...with NIL-A providing no protection. Enhancing the production of collaterals is one thing; enhancing survival is another. What is the evidence, if any, that NIL-A enhances neuronal survival?
You are correct in your analysis of L-dopa. The treatment does have some toxic side effects (which is treated with additional pharmacology) and the approach usually has a limited time span. And you are correct in stating that simply giving a dopamine precursor en masse is surprisingly efficacious. So we're back to square one with NIL-A: unless someone can show me evidence that NIL-A increases the survival of dopaminergic neurons, then the fact that these cells sprout collaterals to, in theory, specifically fill empty target sites, is really a lot of fancy biology to achieve the same thing L-dopa does! |
