title: Protective effect of acetyl-L-carnitine on the apoptotic pathway of peripheral neuropathy.
abstract: Peripheral neuropathies are widespread disorders induced by autoimmune diseases, drug or toxin exposure, infections, metabolic insults or trauma. Nerve damage may cause muscle weakness, altered functionalities and sensitivity, and a chronic pain syndrome characterized by allodynia and hyperalgesia. Pathophysiological mechanisms related to neuropathic disease are associated with mitochondrial dysfunctions that lead to the activation of the apoptotic cascade. In a model of peripheral neuropathy, obtained by the loose ligation of the rat sciatic nerve (CCI), we describe a nerve apoptotic state that encompasses the release of cytochrome C in the cytosol, the activation of caspase 3, and the fragmentation of the genome. Animal treatment with acetyl-L-carnitine (ALCAR), but not with L-carnitine (L-Carn) or Gabapentin, prevents apoptosis induction. ALCAR reduces cytosolic cytochrome C and caspase 3 active fragments expression in a significant manner with respect to saline treatment. Accordingly, ALCAR treatment impairs caspase 3 protease activity, as demonstrated by reduced levels of cleaved PARP. Finally, ALCAR decreases the number of piknotic nuclei. This protection correlates with the induction of X-linked inhibitor apoptosis protein (XIAP). Taken together these results show that CCI is a valuable model to investigate neuropathies-related apoptosis phenomena and that ALCAR is able to prevent regulated cell death in the damaged sciatic nerve.
authors: Department of Preclinical and Clinical Pharmacology, University of Florence, 50139, Florence, Italy. lorenzo.mannelli@unifi.it
authors: Lorenzo
authors: L
authors: Di Cesare Mannelli
authors: C
authors: C
authors: Ghelardini
authors: M
authors: M
authors: Calvani
authors: R
authors: R
authors: Nicolai
authors: L
authors: L
authors: Mosconi
authors: E
authors: E
authors: Vivoli
authors: A
authors: A
authors: Pacini
authors: A
authors: A
authors: Bartolini
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D006930:Hyperalgesia / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology; D018697:Nootropic Agents / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000473:pathology
chemical_list: D018697:Nootropic Agents; D000108:Acetylcarnitine; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3