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Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3‐ and CLN2‐deficient neurons
Author(s) -
Dhar Sumeer,
Bitting Rhonda L.,
Rylova Svetla.,
Jansen Paul J.,
Lockhart Ellen,
Koeberl Dwight D.,
Amalfitano Andrea,
Boustany RoseMary N.
Publication year - 2002
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10143
Subject(s) - neuroprotection , neurodegeneration , batten disease , apoptosis , pharmacology , neurotoxicity , programmed cell death , biology , neuroscience , tunel assay , medicine , biochemistry , toxicity , gene , disease
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‐ and CLN2‐deficient postmitotic hNT neurons at the mitochondrial level. We show that a mechanism of neuroprotection exerted by flupirtine involves complete functional antagonism of N ‐methyl‐ D ‐aspartate or N ‐methyl‐ D ‐aspartate–induced neuronal apoptosis. Flupirtine may be useful as a drug capable of halting the progression of neurodegenerative diseases caused by dysregulated apoptosis.