Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice

Abstract

Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington’s Disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine, CX929, with a short half-life. Injected once daily for 4–7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced the area of intranuclear huntingtin aggregates in R6/2 striatum by 36%. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases.

Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration

“…DARPP-32 is expressed in 96% of the striatal medium-sized spiny neurons and is substantially reduced in HD transgenic mice (64)(65)(66)(67). Consistent with previous reports (64, 67), DARPP-32 immunostaining was 33% lower in striatum of 13-week-old R6/2 mice as compared with their WT littermates ( Figure 8, A and B).…”

Evaluation of Diabetic Rats Behavior after Treatment by <i>Artemisia herba-alba</i> Relative to Insulin

“…While the BHT reveal the elevated depression state of diabetic rats in form of increasing the latency of first grooming episode (LFGE) from (205.9%) 350 s to (100%) 170 s; and the LFGE reduced to (76.5%) 130 s and (88.2%) 150 s in AHA and insulin respectively as shown in Figure 4, same result has been stated by Pires et al, [39] in the introduction section. The VPT revealed Figure 5 and Figure 6, ascertaining this fact the result obtained by Simmons et al, [32] and Tanriover et al, [32] [33]. The general improvement of the behavioral signs among diabetic rats after injection of AHA was ascribed to the new generation of β-cells in the islets of Langerhans of the pancreas as confirmed in histological section done by Yahia et al [27].…”

“…The rats are placed head-up on a cloth-tape covered vertical pole (150 cm long, 3 cm in diameter); when placed on the pole, animals orient themselves downward and descend the length of the pole. Animals with deficits in motor coordination and balance will fall off the pole [32] [33]. Animal time to orient downward (t-turn), reflect of cognitive abilities and the total time the animals stays on the pole (t-total), reflect of motor coordination ability [34] are determined from video recordings for a maximum of 180 seconds.…”

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

“…Brains (n ϭ 5/group) were postfixed, cryoprotected in 20% sucrose/phosphate buffer, and sectioned (40 m, coronal) using a freezing microtome. The sections were processed for immunohistochemical localization of mutant huntingtin protein (1:200; mutant huntingtin protein antibody MAB5374, Millipore), using Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA) and developed using a Dako liquid diaminobenzidine substrate chromogen system (Dako Cytomation) as described previously (35,36). A biotinylated secondary goat anti-mouse antibody was used at 1:500 (Vector Laboratories).…”