Archive for the ‘Neuropathy’ Category

Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy

Comments Off
Posted 15 Jun 2011 — by James Street
Category Alpha Lipoic Acid, Chemotherapy, Cisplatin, docetaxel, Neuropathy

Giorgia Mellia, Corresponding Author Contact Information, E-mail The Corresponding Author, Michela Taianaa, Francesca Camozzia, Daniela Trioloc, Paola Podinic, Angelo Quattrinic, Franco Taronib and Giuseppe Lauriaa

aNeuromuscular Diseases Unit, IRCCS Foundation Neurological Institute “Carlo Besta”, Via Celoria, 11 20133, Milan, Italy

bBiochemistry and Genetics Units, IRCCS Foundation Neurological Institute “Carlo Besta”, Milan, Italy

cSan Raffaele Vita e Salute University, Milan, Italy

Received 27 June 2008;
revised 8 August 2008;
accepted 21 August 2008.
Available online 9 September 2008.

 

Abstract

The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection.

We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.

Keywords: Neurotoxicity; Mitochondria; Chemotherapy; Alpha-lipoic acid; Frataxin

Article Outline

Introduction
Materials and methods
Neuronal cells and Schwann cells cultures
Neuroprotection assay: axonal outgrowth measurement
Neuroprotection assay: neuronal apoptosis
Mitochondrial function assay
Mitochondrial membrane potential changes assay
Electron microscope analysis
Real-time PCR assay
Small interfering RNA experiments
Results
Alpha-lipoic acid protect sensory neurons against paclitaxel and cisplatin induced axonal damage and apoptosis
Paclitaxel and cisplatin neurotoxicity is associated with a reduction of functioning mitochondria in DRG cultures
Alpha-lipoic acid prevents the early loss of membrane potential differential in mitochondria exposed to paclitaxel and cisplatin
Alpha-lipoic acid rescues mitochondrial morphological abnormalities induced by paclitaxel and cisplatin
Alpha-lipoic acid induces frataxin expression in sensory neurons
Discussion
Acknowledgements
References

Neuroprotection During Chemotherapy: A Systematic Review

Comments Off
Posted 15 Jun 2011 — by James Street
Category antioxidants, Chemotherapy, Neuropathy

Walker, Melanie MD*; Ni, Oliver MD†

Abstract

The development of neurotoxicity during antineoplastic therapy is one of the most common reasons for termination or modification of cancer treatment. A number of different agents have been proposed to provide neuroprotection without affecting antitumor efficacy. This review provides an evidence-based summary of neuroprotective medicines, an overview of the literature relating to neuroprotection during cancer treatment and a Neurologist perspective risk assessment and management. Through a systematic review the authors identified 49 papers published to date that report human clinical trials involving potential neuroprotectants in adults. Case reports and series completed in a prospective fashion were also included. Sensory neuropathies were the most prevalent subtype in the literature, and most were at least partially reversible with or without neuroprotective treatment. The majority of study medications had minimal side effects, though 2 trials were prematurely terminated because of adverse patient outcomes. No study reported an effect on antitumor efficacy. Because of the variability in study design, cancer type, outcome measures, and clinical confirmation of neuropathy, meta-analysis could not be appropriately performed. We highlight risk factors and discuss neuropathy screening. Descriptive analysis is provided which reveals that many of the agents studied were likely to confer some at least some neuroprotective benefit.

American Journal of Clinical Oncology:
February 2007 – Volume 30 – Issue 1 – pp 82-92
doi: 10.1097/01.coc.0000239135.90175.4f
Review Article