PMID: 11921051Mar 29, 2002Paper

Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons

Annals of Neurology
Sumeer DharRose-Mary N Boustany

Abstract

Multiple gene defects cause Batten disease. Accelerated apoptosis accounts for neurodegeneration in the late infantile and juvenile forms that are due to defects in the CLN3 and CLN2 genes. Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina. When neurons in late infantile and juvenile brain survive, they manage to do so by upregulating the neuroprotective molecule Bcl-2. The CLN3 gene has antiapoptotic properties at the molecular level. We show that the CLN2 gene is neuroprotective: it enhances growth of NT2 cells and maintains survival of human postmitotic hNT neurons. Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis. The drug flupirtine is a triaminopyridine derivative that acts as a nonopioid analgesic. Flupirtine upregulates Bcl-2, increases glutathione levels, activates an inwardly rectifying potassium channel, and delays loss of intermitochondrial membrane calcium retention capacity. We show that flupirtine aborts etoposide-induced apoptosis in CLN1-, CLN2-, CLN3-, and CLN6-deficient as well as normal lymphoblasts. Flupirtine also prevents the death of CLN3-...Continue Reading

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Citations

Jan 3, 2006·Journal of Biosciences·Subramaniam Ganesh, Shweta Singh
Sep 10, 2005·Apoptosis : an International Journal on Programmed Cell Death·D A Persaud-Sawin, R-M N Boustany
Mar 14, 2009·The Neurologist·Juan M PascualAntonio Gil-Nagel
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Sep 7, 2004·Annals of Neurology·Angela SchulzRose-Mary Boustany
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