RAD140 has been one of my favorite supplements for a while now. I love adding it to my Nootropic stack. It's pretty cool because it's neuroprotective and also gives you GAINS lol. My two favorite things are building muscle and enhancing my cognition. There are side effects to it, it suppresses your testosterone levels so you need to do a quick PCT but I used it for 12 weeks with a couple of Nootropics and noticed an increase in motivation, sexual desire, cognition, memory, focus, endurance, and massive strength gains.
Is anyone here familiar with SARMs? I found a great source that sells bulk powder with COAs which makes it pretty cheap in comparison to others. I usually take 10-20mg. One of the ways I have gotten rid of my anxiety, OCD, and social anxiety is by hitting the gym everyday. It also has been great for boosting my confidence.
As an initial step to evaluate the neuroprotective potential of RAD140, we compared RAD140 with the endogenous androgens T and DHT for their relative abilities to reduce neuron death induced by aggregated Aβ1–42, the peptide implicated in AD neurodegeneration. We found that 24 hours' exposure to Aβ decreased the number of viable neurons by approximately 50%, as compared to vehicle treatment. Consistent with previous observations (47), treatment with T and DHT beginning 1 hour prior to Aβ significantly reduced cell death (Figure 1, A and B). In comparison, treatment of cultures with increasing doses of RAD140 (Figure 1C) or the related SARM RAD192 (Figure 1D) provided similar levels of neuroprotection. The minimum effective concentration of both SARMs was 30 nM whereas T and DHT yielded significant protection at 10 nM.
We previously showed that androgen neuroprotection is limited to insults that involve apoptosis (48). To investigate whether the SARMs mimic this established androgen-protective pathway, we assessed their abilities to reduce cell death induced by 3 insults: Aβ, apoptosis activator II (AAII), and hydrogen peroxide (H2O2). To confirm our prior observations that Aβ and AAII, but not H2O2, induce cell death by caspase-dependent apoptosis in our culture system, we evaluated the ability of the caspase inhibitor zVAD to attenuate cell death. Exposure of cultures to 50 μM zVAD-fmk for 2 hours prior to insult exposure significantly attenuated cell death due to 50 μM Aβ and 3 μM AAII but did not significantly affect cell loss caused by 25 μM H2O2 (Figure 2A). Next, we compared the pattern of protection against the 3 insults by T and the 2 SARMs. Cultures were pretreated for 1 hour with 10 nM testosterone, 100 nM RAD140, or 100 nM RAD192, and then exposed for 24 hours to Aβ, AAII, or H2O2. T (Figure 2B), RAD140 (Figure 2C), and RAD192 (Figure 2D) shared similar protective profiles of significantly protecting against neuronal death induced by Aβ and AAII, but not H2O2.
Androgen-mediated neuroprotection against apoptosis is dependent upon activation of a MAPK/ERK signaling pathway (40). To evaluate the role of MAPK/ERK signaling in mediating the observed neuroprotective effects of SARMs, we first determined whether RAD140 and RAD192 activate MAPK/ERK signaling. Neuronal cultures were exposed for 15 minutes to 10 nM T, 100 nM RAD140, or 100 nM RAD192 in the presence or absence of pretreatment with 10 μM U0126, a MEK inhibitor that blocks MAPK/ERK signaling (49). Western blots with phospho-specific and pan-ERK antibodies show that T, RAD140, and RAD192 induce a significant increase in levels of phosphorylated but not total ERK (Figure 3, A and B). Both the basal levels of ERK phosphorylation and the androgen-mediated increases were significantly attenuated by U0126 (Figure 3, A and B).
We then examined the effect of U0126 inhibition of MAPK/ERK signaling on the extent of neuroprotection by SARMs against Aβ-induced cell death. Pretreatment with 10 μM U0126 completely blocked androgen protection by T, RAD140, and RAD192 (Figure 3C). U0126 alone had no effect on either basal cell viability or the magnitude of Aβ toxicity (Figure 3C).
Based on the cell culture observations, we investigated the neuroprotective potential of RAD140 in vivo. Young adult male rats were randomly assigned to sham-GDX, GDX, GDX+T, and GDX+RAD140 groups that were exposed to the neurotoxin kainate 2 weeks after the initiation of androgen treatments. Following the lesion, seminal vesicles, prostate, and levator ani were removed and weighed to confirm the reported tissue-selective androgen effects of RAD140 (36). GDX resulted in significantly reduced weight of all 3 androgen-responsive tissues, but tissue weights were restored to sham-GDX levels in the GDX+T group (Figure 4, A–C). RAD140 treatment resulted in a nonsignificant increase in the weights of seminal vesicles and prostate, which were still significantly lower than weights observed in the sham-GDX and GDX+T groups. On the other hand, RAD140 significantly increased the weight of the levator ani, an androgen-responsive muscle, to levels similar to those observed in the sham-GDX and GDX+T groups (Figure 4, A–C).
We next investigated whether RAD140 exerts androgenic effects in brain. To accomplish this, we examined androgen regulation of ERα mRNA expression in the hypothalamus, a brain region largely unaffected by kainate. Consistent with prior observations (50), we observed that GDX resulted in increased ERα mRNA expression in comparison to sham-GDX animals. Both GDX+T and GDX+RAD140 groups exhibited significantly decreased ERα mRNA expression relative to the GDX animals (Figure 4D).
To investigate the neuroprotective effects of RAD140 in vivo, the extent of kainate-induced neuron death was assessed by counts of surviving cells immunostained with the neuron-specific antibody NeuN in the CA2/3 region of hippocampus. Relative to vehicle treatment, kainate induced approximately 20% cell loss in the sham-GDX animals (Figure 5, A and B). Neuron survival was significantly reduced in the GDX group, an effect that was prevented by T treatment (Figure 5, C and D; F (3, 29) = 6.93, P < .001). Notably, RAD140 was as effective as T in protecting GDX rats from kainate-induced neuron loss (Figure 5, E and F).
Because kainate induces seizures, we also assessed the effects of the hormonal manipulations on both the latency to seizure onset and maximum seizure severity. The intensity of seizure behavior is known to affect the degree of hippocampal neuron loss. All kainate-treated animals achieved at least level 1 seizure within the 3-hour observation period but none of the vehicle-injected animals showed any seizure-related behaviors. Among the lesioned animals, there was no significant difference across groups in seizure latency (Figure 6A; F (3, 24) = 0.75 P = .53). Similarly, seizure severity did not significantly vary by treatment group (F (3, 26) = 1.36 P = .28), although there was a trend toward reduced severity in the GDX+T and GDX+RAD140 groups (Figure 6B).
