Retinal ischemia is a major cause of vision loss and impairment and a common underlying mechanism associated with diseases such as glaucoma, diabetic retinopathy, and central retinal artery occlusion. The regenerative capacity of the diseased human retina is limited. Our previous studies have shown the neuroprotective effects of intravitreal injection of mesenchymal stem cells (MSC) and MSC-conditioned medium in retinal ischemia in rats. Based upon the hypothesis that the neuroprotective effects of MSCs and conditioned medium are largely mediated by extracellular vesicles (EVs), MSC derived EVs were tested in an in-vitro oxygen-glucose deprivation (OGD) model of retinal ischemia. Treatment of R28 retinal cells with MSC-derived EVs significantly reduced cell death and attenuated loss of cell proliferation. Mechanistic studies on the mode of EV endocytosis by retinal cells were performed in vitro. EV endocytosis was dose-and temperaturedependent, saturable, and occurred via cell surface heparin sulfate proteoglycans mediated by the caveolar endocytic pathway. The administration of MSC-EVs into the vitreous humor 24 h after retinal ischemia in a rat model significantly enhanced functional recovery, and decreased neuroinflammation and apoptosis. EVs were taken up by retinal neurons, retinal ganglion cells,
This is your brain. This is your brain on drugs. Any questions?" With these 12 words the image of sizzling fried eggs was seared into the brains of millions of Americans. The D.A.R.E. era had begun.The Reagan White House set a clear tone that left no room for evidence or inquiry. The first lady was a leading voice in the War on Drugs: "For the sake of our children, I implore each of you to be unyielding and inflexible in your opposition to drugs." And so, children of the '80s were bombarded with scare tactics and urban legends that masqueraded as "education." Coupled with dog whistles about "inner city crime," drug policy became both rigid and intensely politicized.This prohibitionist approach stood in contrast to a long history of research on the psychoactive properties of drugs. Freud experimented with cocaine to "untie his tongue." Bill Wilson, co-founder of Alcoholics Anonymous, credited insights from LSD with helping him fight addiction. The CIA, on a more dystopian path, tested a wide range of drugs for mind control and interrogation with its classified MK-Ultra project. This devolved into LSD inexplicably appearing in brothels and bottles of Cointreau as covert dosing of psychedelics became an occupational hazard at the CIA (1).Amid this frenzy was MDMA (3,4-methylenedioxymethamphetamine). First synthesized in 1912, the drug was largely overlooked until its "rediscovery" in the 1970s by chemist Alexander Shulgin. Shulgin was researching serotonergic amphetamine analogs. He also had an inclination for ingesting his end product. He found its "lightening" effects unique and passed it along to fellow researchers and friends, including retired psychotherapist Leo Zeff. Zeff was so impressed that he abandoned retirement to become MDMA's Johnny Appleseed, spreading it to thousands in the psychotherapy community. Some therapists and patients came to swear by the drug's effectiveness, touting it for enhancing insight without inducing fear.Their timing was poor. Shulgin and Zeff's work emerged in the wake of the Vietnam War. Anti-war protesting and increasing recreational drug use in hippie and student movements was followed by a tremendous conservative backlash. President Nixon labeled Timothy Leary the "most dangerous man in America" for urging youth to "turn on, tune in, drop out." The government passed the Controlled Substances Act of 1970, thereby creating our current scheduling system and criminalizing unlawful possession. As part of the process, they created a commission with the specific goal of studying cannabis. The committee concluded that cannabis should be decriminalized; instead, bowing to political pressure, it was placed in Schedule I along with LSD and heroin. The motives for this work were carefully calculated and had nothing to do with science. As John Ehrlichman, Nixon's Domestic Affairs
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