Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington's disease

• Published in: Journal of the neurological sciences 2005-04, Vol.231 (1), p.57-66
• Main Authors: Wang, Xukui, Sarkar, Aparajita, Cicchetti, Francesca, Yu, Meixiang, Zhu, Aijun, Jokivarsi, Kimmo, Saint-Pierre, Martine, Brownell, Anna-Liisa
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Binding, Competitive - drug effects; Biological and medical sciences; Body Weight - genetics; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Chemistry - genetics; Brain Mapping; Cellular inclusion; Cerebral Cortex - diagnostic imaging; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Cystamine; Cystamine - therapeutic use; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine Antagonists - pharmacology; Dopamine D2 receptor; Dose-Response Relationship, Drug; Drug Interactions; Fluorodeoxyglucose F18 - pharmacokinetics; Glucose - metabolism; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntington's disease; Image Processing, Computer-Assisted; Inclusion Bodies - pathology; Male; Medical sciences; Mice; Mice, Transgenic; Motor Activity - physiology; Neurology; Neuroprotection; Neuroprotective Agents - therapeutic use; Peptides - genetics; Positron-Emission Tomography; Raclopride - pharmacology; Transglutaminases - antagonists & inhibitors; Tritium - pharmacology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2004.12.011

To investigate efficacy of cystamine induced neuroprotection, we conducted PET imaging studies of cerebral glucose metabolism with [ 18F]FDG (2-deoxy-2-[ 18F]fluoro- d-glucose) and striatal dopamine D2 receptor function with [ 11C]raclopride in R6/2 transgenic Huntington mice. In the control mice, exponentially decreasing glucose utilization was observed in the striatum N str [SUV]=(41.75±11.80) 58,str*exp(−(0.041±0.007) *t [days]); cortex N cort [SUV]=24.14±3.66) 58,cort*exp(−(0.043±0.007)* t [days]); and cerebellum N cer [SUV]=(34.97±10.58) 58,cer*exp(−(0.037±0.008)* t [days]) as a function of age starting at 58 days. Given that the underlying degeneration rate in the cystamine treated mice is similar to that observed in control animals, the protection coefficient ( β) calculated from the equation N t = N 58*exp(−(1− β)* k* t) was 0.133±0.035 for the striatum; 0.122±0.028 for the cortex and 0.224±00.042 for the cerebellum with a dose of 100 mg/kg. The 50 mg/kg cystamine dose provided significant protection only for the striatum and only minor protection was obtained using lower doses. Striatal binding potential of [ 11C]raclopride was 1.059±0.030 in the control mice, and enhanced in the cystamine treated animals in a dose dependent manner up to 1.245±0.063 using the 100 mg/kg dose. Histological analysis confirmed cystamine induced neuroprotection of striatal and cortical neurons and Nissl staining revealed that formation of cellular inclusions was reversed in a dose dependent manner. Cerebral imaging and histological evidence support the use of cystamine as a neuroprotective agent for Huntington's disease (HD) pathology.