Chronic 3-Nitropropionic Acid Treatment in Baboons Replicates the Cognitive and Motor Deficits of Huntington’s Disease

Abstract

We showed recently that chronic administration of the mitochondrial inhibitor 3-nitropropionic acid (3NP) in primates produces various dyskinetic movements and dystonic postures associated with selective striatal lesions displaying many similarities with the pathological features of Huntington's disease (HD). In the present study, we examined whether such a toxic treatment could also induce frontal-type deficits similar to those observed in HD patients. Cognitive performances of 3NP-treated and control baboons were compared using the object retrieval detour task (ORDT), a test designed to assess the functional integrity of the frontostriatal pathway in human and nonhuman primates. During the same time, the motor function of each animal was assessed under spontaneous "no drug" conditions, and time-sampled neurological observations were used after apomorphine administration. A significant impairment in the ORDT was observed in the 3NP animals after 3-6 weeks of treatment, occurring in the absence of spontaneous abnormal movements by in the presence of apomorphine-inducible dyskinesias. Prolonged 3NP treatment resulted in the progressive appearance of spontaneous abnormal movements. Histological evaluation of these animals showed selective bilateral caudate-putamen lesions with sparing of the cerebral cortex, notably the prefrontal cortex. The present study demonstrates that chronic 3NP treatment replicates in primates the basic pathophysiological triad of HD, including spontaneous abnormal movements, progressive striatal degeneration, and a frontostriatal syndrome of cognitive impairment.

Protective effect ofConvolvulus pluricaulisstandardized extract and its fractions against 3-nitropropionic acid-induced neurotoxicity in rats

“…3-NP treatment significantly caused cognitive dysfunction as demonstrated by the results of MWMT (delayed transfer latency and decreased time spent in the target quadrant). These findings are in agreement with earlier reports suggesting a variety of neurobehavioral abnormalities and cognitive deficits after 3-NP administration (Kumar & Kumar, 2009b;Palfi et al, 1996). It has also been reported that 3-NP produces lesion in hippocampal CA1 and CA3 pyramidal neurons, areas of the brain associated with cognitive task (Sugino et al, 1999).…”

Basal Ganglia Output and Cognition: Evidence from Anatomical, Behavioral, and Clinical Studies

“…Primates given chronic low doses of MPTP (to mimic Parkinson's disease) or 3-NP (to mimic Huntington's disease) display profound cognitive and visual deficits prior to the development of gross motor impairments (see Schneider & Roeltgen, 1993;Roeltgen & Schneider, 1994;Schneider & Pope-Coleman, 1995;Palfi et al, 1996). These results, along with those from selective lesions of the sensorimotor and associative portions of the primate striatum (e.g., Divac et al, 1967;Miyachi et al, 1997), support the concept that basal ganglia systems contain separate motor and cognitive circuits.…”

Toxicity of Dopamine to Striatal Neurons In Vitro and Potentiation of Cell Death by a Mitochondrial Inhibitor

“…The Dl receptors are positively can be generated by dopamine autoxidation or through coupled to adenylyl cyclase, and phosphorylation of the action of monoamine oxidase, a mitochondrial encalcium channels by protein kinase A increases wholezyme (Graham eta!., 1978;Graham, 1984). Autoxidacell calcium currents and can consequently lead to a tion leads to production of hydroxyl and superoxide rise in intracellular Ca 2~concentration (Trautwein and radicals, hydrogen peroxide (which can form hydroxyl Hescheler, 1990;Hartzell et al, 1991). The D2 recepradicals in the presence of transition metals such as tors are negatively coupled to adenylyl cyclase, and iron), and quinones (Graham, 1984).…”