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FutureStarrA Rad 140
RAD-140, also known as Testolone, has been tested for its abilities to increase muscle mass, chest, and upper arm circumference, as well as strength and power. Researchers also revealed that the drug increased bone mineral density by approximately three percent.
) with an X-Y step of 150 μm × 150 μm was used for cell counts. Only cells with positively stained nuclei were counted, not dead or dying cells or cells that were on the upper or lower edge of the section the cytoplasm of which was stained but appeared without a nucleus. To control for variability in the number of sections analyzed, the total number of NeuN-immunoreactive nuclei in each animal was divided by the number of sections assessed and then expressed as a percentage of neurons counted in the sham-GDX, nonlesioned group. Of the 24 rats that received kainate and survived the kainate-induced seizures, 2 were excluded from analyses because they showed extensive loss of CA1 neurons indicating hypoxic injury, which is known to occur in a subset of lesioned animals (46).
Androgens exert numerous beneficial actions in brain by several distinct mechanisms (18). Many, but not all, neural androgen actions involve AR activation, which triggers a wide range of rapid cell-signaling pathways as well as classic genomic regulation (58). Because SARMs can interact with AR differently than endogenous androgens, the efficacy of specific SARMs in activating defined androgenic pathways is a key consideration in pursuing translational goals. In terms of androgen neuroprotection, our prior work has defined a mechanism that is both dependent upon MAPK/ERK signaling pathway (40) and limited in protective efficacy to apoptosis (48). Our findings with RAD140 and the related compound RAD192 demonstrate that both SARMs mimic this established mechanism of neuroprotection in cultured neurons: they activate MAPK/ERK signaling as evidenced by ERK phosphorylation, their neuroprotection is blocked by pharmacologic inhibition of MAPK signaling, and they protect against 2 apoptotic insults but not a nonapoptotic insult. MAPK/ERK signaling is also known to contribute to androgen protection in non-neural cells (59, 60). In adult male rats depleted of endogenous androgens by GDX, RAD140 matched the neuroprotection observed with T against kainate, a neurotoxin known to kill hippocampal neurons via apoptosis (61). Because neither T nor RAD140 significantly affected kainate-induced seizure behavior, a variable that can alter lesion severity (38), these observations suggest a direct mechanism of androgen neuroprotection consistent with our prior observations (39). (Source: www.ncbi.nlm.nih.gov)
One significant limitation of androgen therapy is the potential for increased risk of developing prostate cancer and or accelerated growth of existing prostate tumors. To overcome this problem, new classes of synthetic testosterone-like compounds, called “selective androgen receptor modulators” (SARMs), have been developed (30, 31). SARMs are ligands for AR that exert limited effects in prostate and other reproductive tissues but have potent androgenic actions in muscle and bone (32, 33). Although SARMs such as 7α-methyl-19-nortestosterone undergo enzymatic aromatization to yield metabolites that bind to ER (34), most of the currently available SARMs are poor substrates for aromatase and interact specifically with AR (35). The possible utility of SARMs for therapeutic use in AD and other neural disorders has only recently begun to be investigated.
Male Sprague Dawley rats (n = 8 per group) were purchased gonadectomized (GDX) and sham-GDX at 3 months of age (Harlan Laboratories, Inc.). All animals were housed individually with ad libitum access to food and water under a 12 hour light, 12 hour-dark cycle. Animals underwent GDX 14 days prior to the start of treatment, allowing for the depletion of endogenous hormones. For testosterone (T) treatment, GDX male rats were implanted with a 30-mm length SILASTIC capsule (1.47 mm inner diameter × 1.96 mm outer diameter; Dow Corning) packed with dry T to a length of 20 mm and capped on both ends with 5 mm of silicone glue. Vehicle-treated animals were implanted with an empty capsule with the same dimensions. For SARM treatment, GDX rats were administered 1 mg/kg RAD140 suspended in 0.5% methyl cellulose (1 mg/mL) by daily oral gavage for 2 weeks. This dose was chosen based on previous reports for RAD140 efficacy (36). Vehicle-treated animals were gavaged with a similar weight/volume of 0.5% methyl cellulose. On day 13 of the 2-week hormone treatment period, kainate (10 mg/kg; Enzo Life Sciences) or sterile water control was injected ip. Kainate was dissolved immediately prior to use in sterile water and lightly heated to fully solubilize. On day 14, SARM-treated rats were administered 1 mg/mL of RAD140 suspended in safflower oil by sc injection because oral gavage is difficult following kainate lesion. (Source: www.ncbi.nlm.nih.gov)