Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca : observation from a randomized controlled trial

Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have suggested that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood. Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo. In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms. This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at http://clinicaltrials.gov (NCT02914769)

The prion protein knockout mouse: a phenotype under challenge

The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression : a randomized placebo-controlled trial

Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-angstrom sberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054). Conclusions To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression494655663CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES466760/2014; 479466/2011677/2012; 1577/201

Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrPC-deficiency

The Sprn gene encodes Shadoo (Sho), a glycoprotein with biochemical properties similar to the unstructured region of cellular prion protein (PrPC). Sho has been considered a candidate for the hypothetical π protein that supplies a PrPC-like function to maintain the viability of Prnp0/0 mice lacking the PrPC protein. To understand these relationships more clearly we probed the cell biology of Sho and created knockout mice. Besides full-length and a “C1” C-terminal fragment, we describe a 6-kDa N-terminal Sho neuropeptide, “N1,” which is present in membrane-enriched subcellular fractions of wild-type mice. Sprn null alleles were produced that delete all protein coding sequences yet spare the Mtg1 gene transcription unit that overlaps the Sprn 3′ UTR; the resulting mice bred to homozygosity were viable and fertile, although Sprn0/0 mice maintained in two genetic backgrounds weighed less than wild-type mice. Lack of Sho protein did not affect prion incubation time. Contrasting with lethality reported for knockdown of expression in Prnp0/0 embryos using lentiviruses targeted against the Sprn 3′ UTR, we established that double-knockout mice deficient in both Sho and PrPC are fertile and viable up to 690 d of age. Our data reduce the impetus for equating Sho with the notional π protein and are not readily reconciled with hypotheses wherein expression of PrPC and Sho are both required for completion of embryogenesis. Alternatively, and in accord with some reports for PrPC, we infer that Sho’s activity will prove germane to the maintenance of neuronal viability in postnatal life

A PrPC-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor

The cellular prion protein, PrP(C), is a glycosylphosphatidylinositol-anchored protein, abundant in lipid rafts and highly expressed in the brain. While PrP(C) is much studied for its involvement under its abnormal PrP(Sc) isoform in Transmissible Spongiform Encephalopathies, its physiological role remains unclear. Here, we report that GSK3β, a multifunctional kinase whose inhibition is neuroprotective, is a downstream target of PrP(C) signalling in serotonergic neuronal cells. We show that the PrP(C)-dependent inactivation of GSK3β is relayed by a caveolin-Lyn platform located on neuronal cell bodies. Furthermore, the coupling of PrP(C) to GSK3β potentiates serotonergic signalling by altering the distribution and activity of the serotonin 1B receptor (5-HT(1B)R), a receptor that limits neurotransmitter release. In vivo, our data reveal an increased GSK3β kinase activity in PrP-deficient mouse brain, as well as sustained 5-HT(1B)R activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP(C) signalling that strengthens neurotransmission