RespireRx Pharmaceuticals Inc (RSPI): YMB/Gfp: AMPA-Receptors & calpain mediat...

Reply Private New

Next 10 Prev Next

Send PM Follow Ignore

Followers	16
Posts	4127
Boards Moderated	2
Alias Born	07/22/2004

Aiming4

Re: None

Sunday, 11/27/2005 1:20:43 AM

Sunday, November 27, 2005 1:20:43 AM

YMB/Gfp: AMPA-Receptors & calpain mediated spectrin breakdown

Re: Long-term Exposure?
by: gfp927z
Long-Term Sentiment: Strong Buy 11/26/05 10:53 pm
Msg: 22660 of 22663

Concerning potential problems resulting from long term dosing of Ampakines -

There have been several papers published linking prolonged positive modulation of AMPA receptors to calpain mediated spectrin breakdown (a process associated with protein degradation and neuro/synaptic degeneration). That *might* be what the Stanford doctor was referring to. Abstracts relating to this were previously posted here on the board. Here's a link at PubMed -

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15784649&query_hl=2

We don't have much to go on, but it sounded like this phenomenon was associated more with the high impact approach. Other hurdles facing the high impact approach are excitotoxicity and the feedback loop phenomenon.

http://finance.messages.yahoo.com/bbs?.mm=FN&action=m&board=1604243276&tid=cor&sid=1...

Long term effects (cont)
by: gfp927z
Long-Term Sentiment: Strong Buy 11/26/05 10:59 pm
Msg: 22662 of 22663

I hope Neuro doesn't mind me re-posting his post from last year on the calpain subject. He spoke with Gary Lynch directly and asked him about it -

Recommend this Post - This post has 12 recommendations Ignore this User | Report Abuse
Re: lynch paper
by: Neuroinv 12/07/04 04:56 pm
Msg: 17204 of 22660

My initial reaction to the paper was 'uh oh', since calpain is a protease involved in apoptosis (programmed cell death). One would not want to see unbridled calpain production, Cortex has had rights to calpain inhibitors intended for stroke, but they never went anywhere, other than to Alkermes and then back. However, since spectrin is involved in forming the structural elements of the neuronal spines where the synapses are located, I wondered if calpain is in fact necessary for undoing previous structures so that new structures can be 'built' as a result of LTP. In other words, some calpain production is necessary for synaptic plasticity, the changes that occur with learning.

But I wanted to make sure, so I asked Gary Lynch. While his response was infinitely more sophisticated than this sparse summary, the bottom line is that (at least some) Ampakines do promote calpain production, which deconstructs spectrin, which allows the configuration to reform. He also confirmed that longterm CX717 studies showed none of the deleterious effects that would occur if there was excessive calpain production.

NeuroInvestment

http://finance.messages.yahoo.com/bbs?.mm=FN&action=m&board=1604243276&tid=cor&sid=1...

Re: Long term effects (cont)
by: gfp927z
Long-Term Sentiment: Strong Buy 11/26/05 11:04 pm
Msg: 22663 of 22663

Here's a Lynch abstract on the subject -

1: Neurochem Int. 2005 Jan;46(1):31-40. Related Articles, Links

Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices.

Jourdi H, Yanagihara T, Martinez U, Bi X, Lynch G, Baudry M.

Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA; Department of Psychiatry and Human Behavior, University of California at Irvine Medical School, Irvine, CA 92697-1695, USA.

Positive modulators of AMPA receptors (AMPAr), also known as ampakines, are allosteric effectors of the receptors and have been extensively studied in past years due to their potential use as treatment for various diseases and ailments of the central nervous system such as mild cognitive impairment, schizophrenia, and Alzheimer's disease. Ampakines have been shown to improve performance on memory tasks in animals and in human subjects, an effect linked to their ability to increase agonist-mediated ion influx through AMPAr, thus leading to enhanced synaptic responses and facilitation of long-term potentiation (LTP) induction at glutamatergic synapses. As LTP is associated with calpain activation and spectrin degradation, we determined the effects of ampakine treatment of cultured hippocampal slices on spectrin degradation. Calpain activation was evaluated by determining the levels of the 145-150kDa degradation products of spectrin. Our data indicated that incubation of hippocampal slices with some, but not all positive modulators of AMPA receptors resulted in enhanced spectrin degradation, an effect that was blocked by a calpain inhibitor. In addition, an antagonist of AMPAr but not of NMDAr blocked ampakine-induced spectrin degradation. These results indicate that prolonged treatment with selected ampakines leads to spectrin degradation mediated by activation of the calcium-dependent protease calpain.

PMID: 15567513 [PubMed - in process]

http://finance.messages.yahoo.com/bbs?.mm=FN&action=m&board=1604243276&tid=cor&sid=1...

#Board-3252