CX614 explained

CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.^[1]

Chronic CX-614 treatments produce rapid increases in the synthesis of the brain-derived neurotrophic factor BDNF which has very important effects on synaptic plasticity^[2] and may have applications in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Acute CX-614 treatments activate local mRNA translation (new protein synthesis) within dendrites^[3] and this is mediated by a fast upregulation of BDNF release. CX-614-dependent release of BDNF rapidly increases translation of proteins that are important for synaptic plasticity such as ARC/Arg3.1 and CaMKIIalpha.

CX-614 has also been proposed as a treatment for conditions such as depression and schizophrenia,^{[4] [5]} but produces receptor downregulation following chronic administration, which might limit the potential for extended use.^{[6] [7]}

However, downregulation of AMPA receptors with prolonged CX-614 administration can be avoided by designing and using short and intermittent treatment protocols, which could still upregulate BDNF protein levels without reducing the levels of AMPA receptors.^[8]

Importantly, such short and intermittent treatment protocols are neuroprotective against neurotoxicity induced with MPTP and MPP⁺ in cultured midbrain (mesencephalic) and hippocampal organotypic slices.^[9]

These results uncovered the neuroprotective effects of CX-614 and indicated that opened the way for further experimentation with CX-614 as an important new treatment for Parkinson's disease and Alzheimer's disease.

CX-614 has also been shown to reduce the behavioural effects of methamphetamine in mice, and may have application in the treatment of stimulant abuse.^[10]

See also

• AMPA receptor positive allosteric modulator

Notes and References

1. Arai AC, Kessler M, Rogers G, Lynch G . Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466 . Mol. Pharmacol. . 58 . 4 . 802–13 . 2000 . 10999951 . 10.1124/mol.58.4.802. 6489143 .
2. Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM . Chronic elevation of brain-derived neurotrophic factor by ampakines . J Pharmacol Exp Ther . 307 . 1 . 297–305 . Oct 2003 . 12893840 . 10.1124/jpet.103.053694 . 1235935 .
3. Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M . POSITIVE AMPA RECEPTOR MODULATION RAPIDLY STIMULATES BDNF RELEASE AND INCREASES DENDRITIC mRNA TRANSLATION . J. Neurosci. . 29 . 27 . 8688–8697 . Jul 2009 . 19587275 . 10.1523/JNEUROSCI.6078-08.2009 . 2761758 .
4. Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM . Mechanism of positive allosteric modulators acting on AMPA receptors . J. Neurosci. . 25 . 39 . 9027–36 . Sep 2005 . 16192394 . 10.1523/JNEUROSCI.2567-05.2005 . 6725607 .
5. Lynch G . Glutamate-based therapeutic approaches: ampakines . Curr Opin Pharmacol . 6 . 1 . 82–8 . Feb 2006 . 16361116 . 10.1016/j.coph.2005.09.005 .
6. Jourdi H, Lu X, Yanagihara T . Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices . J Pharmacol Exp Ther . 314 . 1 . 16–26 . Jul 2005 . 15784649 . 1554891 . 10.1124/jpet.105.083873 . etal.
7. Mitchell NA, Fleck MW . Targeting AMPA Receptor Gating Processes with Allosteric Modulators and Mutations . Biophys. J. . 92 . 7 . 2392–402 . Apr 2007 . 17208968 . 1864835 . 10.1529/biophysj.106.095091 . 2007BpJ....92.2392M .
8. Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression . Neuroscience . 159 . 1 . 283–295 . Mar 2009 . 19141314 . 2746455 . 10.1016/j.neuroscience.2008.12.018 . Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM .
9. Jourdi H, Hamo L, Oka T, Seegan A, Baudry M . BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP⁺-induced toxicity in cultured hippocampal and mesencephalic slices . Neuropharmacology . 56 . 5 . 876–885 . Apr 2009 . 19371576 . 10.1016/j.neuropharm.2009.01.015 . 3659791 .
10. Hess US, Whalen SP, Sandoval LM, Lynch G, Gall CM . Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion . Neuroscience . 121 . 2 . 509–21 . 2003 . 14522010 . 10.1016/S0306-4522(03)00423-8. 23287000 .