In This Issue pubs.acs.org/chemneuro
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ENDOCANNABINOID MIMICS THAT INHIBIT NEUROINFLAMMATION
dependence to methamphetamine (DOI: 10.1021/acschemneuro.6b00389). Here, the authors assemble a vaccine against the effects of methamphetamine on the central nervous system. As methamphetamine alone does not elicit an immune response, an inactive homologue of the drug must be conjugated to an immunogenic protein. The protein, such as keyhole limpet hemocyanin (KLH), promotes activation of antibody-generating immune cells, while the drug homologue acts as a hapten to ensure that the resulting antibodies are specific for methamphetamine (without producing the psychoactive effects of the drug). A series of various amino-acid linkers were employed to connect the two vaccine components and test efficacy against the effects of methamphetamine. It was found that different linkers can “tune” the effects of the vaccine, producing antibodies of varying concentration and affinity for the drug. One version, however, was able to effectively sequester methamphetamine in mouse serum, reducing drug concentration in the brain.
A plethora of CNS-related disorders result from neuroinflammation, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and stroke. Considerable evidence suggests that long chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) possess neuroprotective properties that inhibit inflammation. In this issue, Wang et al. (DOI: 10.1021/acschemneuro.6b00298) construct DHA-derivatives to combat the neuroinflammatory effects of lipopolysaccharide (LPS). Previous studies by the authors have shown that amides derived from fatty acids such as DHA may also confer protection from inflammation. Furthermore, conjugation of fatty acid amides with dopamine affords the less well-studied N-acyl dopamine moiety, which can display cannabimimetic properties that inhibit some of the downstream effects of LPS-induced inflammation. Here, the authors show that fatty acid conjugates containing N-acyl dopamine effectively attenuate inflammatory regulators in microglial cells. Additionally, these conjugates reduced the symptoms of Parkinson’s disease in mouse models.
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Some neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), are genetically based: nucleotide repeat expansions such as the GGGGCC hexanucleotide repeat (HR) underlying ALS can alter local chromatin structure and gene expression. Transcription of GGGCC HRs can lead to loss of function as the essential genes they are intruding are improperly expressed. Furthermore, the antisense transcripts (CCCCGG) can also occur, and form nuclear foci in the central nervous system that sequester RNA binding proteins essential for normal cellular function. The presence and expression of excessive nucleotide repeat expansions trigger a complex array of cellular dysfunction that maintains disease progression. In this issue, Zhang et al. (DOI: 10.1021/acschemneuro.6b00348) structurally characterize the nature of these ALS hexanucleotide repeats in DNA, RNA, sense, and antisense sequences. Molecular dynamics simulations reveal atypical structures for several duplexes arising from different reading frames. Nucleotide motifs varied considerably in structure and stability, arising from different base pair mismatches based on
BUILDING A “METH VACCINE” TO FIGHT ADDICTION
The widespread abuse of psychoactive drugs such as methamphetamine is one of the most significant health crises facing us today. Chemical dependence and severe withdrawal symptoms exacerbate the issue and make drug abstinence difficult to maintain for those who suffer from substance abuse. Janda and co-workers, who have previously reported the synthesis of an “opioid vaccine,” now apply the principle of exploiting the immune response in the battle against drug © 2017 American Chemical Society
GENETIC MECHANISMS OF NEURODEGENERATIVE DISORDERS
Published: March 15, 2017 424
DOI: 10.1021/acschemneuro.7b00082 ACS Chem. Neurosci. 2017, 8, 424−425
ACS Chemical Neuroscience
In This Issue
whether they contained G-rich or C-rich sequences. These data provide further molecular understanding of the HR expansions that cause neurodegenerative disease.
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DOI: 10.1021/acschemneuro.7b00082 ACS Chem. Neurosci. 2017, 8, 424−425
