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Re: Memory-Long, but...

Posted by Adam on November 17, 1999, at 22:45:32

In reply to Re: Memory -- not of YBMV, posted by dj on October 27, 1999, at 1:09:57

Anyway, more examples:

-I'm working on giving a talk to the whole department, which happens 2-3 times a year.
I'm looking at some of my slides that I made a few days ago, and it's like I'm seeing them
for the first time. I'm getting a tad anxious...this is not normal.

-I met some people for a movie last night (Being John Malkovitch; by the way...YOU MUST SEE
THIS MOVIE) and had a woman I met at a Halloween party introduce herself to me again. It
seems we spoke for about half an hour. I could not remember her at all, not the conversation,
nothing. She was really sweet. I would have remembered, normally. Now I feel like a yutz.

-I can't remember where I park my car, ever. It doesn't seem to matter what I do. Unless I
draw myself a map before I leave the parking lot, no way. I know this is a common problem,
but it's getting beyond weird for me. I've lost almost all sense of direction.

OK, again, maybe I'm being paranoid, but I don't think so. I know I can do better than this.
The above examples are just a few of a host that I could rattle off, so just think of how many
I forgot.

Anyway, a couple months ago, I ran across this paper while flipping through Nature:

Nature 1999 Sep 2;401(6748):63-9

Genetic enhancement of learning and memory in mice.

Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ

Department of Molecular Biology, Princeton University, New Jersey 08544-1014, USA.

Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic
coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory
formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains
of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in
learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation.
NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic
enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.

I didn't think much about it then, except that it was very interesting and exciting. But worries
about my slides triggerd a thought and I got on Medline with a hunch. I turned up some reports
on the subject of selegiline and the NMDA receptor, and found a couple suggesting an interaction.

The NMDA receptor is a channel controlling Ca2+ flux into the neuron. When this receptor binds
glutamate, it triggers long-term potentiation of neurons in the hippocampus, which is thought to be
an essential process in learning. NMDA receptor antagonists have been shown to inhibit LTP and
(interestingly)spacial learning. Also, reduced expression of another subunit of the NMDA receptor
yields mice that behave similarly to mice in chemically-induced schizophrenia models.

I the abstracts discussing selegiline, it would appear that selegiline can protect against excitotoxicity
seen under certain conditions that are known to involve NMDA-receptor agonism (indirect induction of NMDA
agonist or direct treatment with NMDA). Two of the abstracts describe experiments that show convincingly
that selegiline's neuroprotective properties are not related to its MAOI properties or protection
against oxidative stress caused by free radicals known to be produced in neuron excitotoxicity. Another
states that MAO-B inhibition is an unlikely source of the protective effect, but provides no rationale.

At any rate, it seems that selegiline might operate somehow as an NMDA receptor antagonist. It seems reasonable
to conclude that this might have deleterious effects on memory. In the case of neurodegenerative diseases,
the beneficial protective effect might more than offset the mechanistic complications, but that's not my
particular problem.

So, if this is the case, what, if anything, could one do about it? I don't thing trying to take an NMDA receptor
agonist (even if such things were available as a drug) would be a good idea because of neurotoxicity. I would think
it would be impossible to properly titrate the dose to counteract selegiline-inhibition, if such a thing is even
possible. I'm stumped. At the same time, I think this idea might have some merit.

Any thoughts?

PMID: 10448922, UI: 99376152

L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro.

Mytilineou C, Radcliffe P, Leonardi EK, Werner P, Olanow CW

Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.

L-Deprenyl is a relatively selective inhibitor of monoamine oxidase (MAO)-B that delays the emergence of disability and the progression of signs and symptoms of Parkinson's disease.
Experimentally, deprenyl has also been shown to prevent neuronal cell death in various models through a mechanism that is independent of MAO-B inhibition. We examined the effect
of deprenyl on cultured mesencephalic dopamine neurons subjected to daily changes of feeding medium, an experimental paradigm that causes neuronal death associated with
activation of the NMDA subtype of glutamate receptors. Both deprenyl (0.5-50 microM) and the NMDA receptor blocker MK-801 (10 microM) protected dopamine neurons from
damage caused by medium changes. The nonselective MAO inhibitor pargyline (0.5-50 microM) was not protective, indicating that protection by deprenyl was not due to MAO
inhibition. Deprenyl (50 microM) also protected dopamine neurons from delayed neurotoxicity caused by exposure to NMDA. Because deprenyl had no inhibitory effect on NMDA
receptor binding, it is likely that deprenyl protects from events occurring downstream from activation of glutamate receptors. As excitotoxic injury has been implicated in
neurodegeneration, it is possible that deprenyl exerts its beneficial effects in Parkinson's disease by suppressing excitotoxic damage.

J Neurosci Res 1998 Apr 15;52(2):240-6

Increased neuronal cell survival after L-deprenyl treatment in experimental thiamine deficiency.

Todd KG, Butterworth RF

Neuroscience Research Unit, Andre-Viallet Clinical Research Centre, Hopital St-Luc (University of Montreal), Quebec, Canada.

Experimental thiamine deficiency results in a reproducible pattern of selective neuronal cell death. Events such as blood-brain barrier breakdown, N-methyl-D-aspartic acid (NMDA)
receptor-mediated excitotoxicity, and increased reactive oxygen species have been implicated in thiamine deficiency-induced neural loss. L-deprenyl protects dopaminergic,
noradrenergic, and acetylcholinergic neurons from neurotoxic, mechanical, and excitotoxic damage. In the present study, the effects of l-deprenyl on neuronal cell survival were
examined in rats made thiamine deficient by daily administration of the central thiamine antagonist pyrithiamine (0.5 mg/kg s.c.). Rats assigned to thiamine deficient or control groups
received daily injections of l-deprenyl (0.25, 0.5, or 1.0 mg/kg/day i.p.) or vehicle until they reached a state of severe thiamine deficiency (loss of righting reflex). At this stage, thiamine
status was restored by daily injections of thiamine (10 mg/kg s.c.) for 3 days, after which the animals were killed, and their brains were processed for neuronal cell counts (cresyl violet
staining), astrocytic proliferation [glial fibrillary acidic protein (GFAP) immunohistochemistry], and monoamine oxidase B (MAO-B) activity. All rats receiving l-deprenyl (all doses) had
significantly decreased neuronal cell loss in thalamic nuclei, in the inferior colliculus, and in the inferior olive and had a concomitant decrease in reactive astrocytic proliferation compared
with the thiamine-deficient, vehicle-treated rats. The neuroprotective effects of l-deprenyl in thiamine deficiency induced brain damage most likely result from its properties other than its
effects as an MAO-B inhibitor.

PMID: 9579414, UI: 98239017

Eur J Pharmacol 1999 Jul 14;377(1):29-34

Deprenyl rescues dopaminergic neurons in organotypic slice cultures of neonatal rat mesencephalon from
N-methyl-D-aspartate toxicity.

Shimazu S, Katsuki H, Akaike A

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.

The potential neuroprotective effect of (-)-deprenyl (R-N,alpha-dimethyl-N-2-propynylbenzeneethanamine) against N-methyl-D-aspartate (NMDA) excitotoxicity was investigated on
rat mesencephalic dopaminergic neurons in organotypic slice cultures. While 24 h application of NMDA (100 microM) caused a marked decrease in the number of surviving
dopaminergic neurons, simultaneous application of (-)-deprenyl significantly attenuated the cytotoxic effect of NMDA. (+)-Deprenyl showed a less potent but still significant protective
effect against NMDA insult. Pre-treatment of cultures with (-)-deprenyl conferred no protection against subsequent NMDA insult, suggesting that the protective effect of (-)-deprenyl
may be independent of its irreversible inhibitory action on monoamine oxidase B. (-)-Deprenyl was also ineffective in preventing cell death induced by H2O2. These results indicated
that (-)-deprenyl protects dopaminergic neurons from NMDA excitotoxicity through a mechanism distinct from monoamine oxidase inhibition or detoxification of reaction oxygen




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