Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 8 • December 2012


Improved Cognition in Aged Animals

Sigma-1 Receptor Chaperones Regulate the Secretion of BDNF: DHEA and pregnenolone as sigma-1 receptor agonists

A 2012 paper1 reports new data showing that the sigma-1 receptor chaperone (found in the endoplasmic reticulum where proteins are synthesized and folded) regulates the secretion of brain-derived neurotrophic factor, which has as one of its functions the promotion of adult neurogenesis. Other work described below identifies dehydroepiandrosterone (DHEA) as an agonist (activator) of the sigma-1 receptor, whereas progesterone was found to be a potent antagonist (inhibitor) of the receptor.

“The sigma-1 receptor (Sig-1R) is a novel endoplasmic reticulum (ER) molecular chaperone that regulates protein folding and degradation. The Sig-1R activation by agonists is known to improve memory, promote cell survival, and exert an antidepressant-like action in animals.”1 Maintenance of proper protein folding is a critical form of quality control that is impaired with aging.

The Sig-1R is also reported to be involved in neuronal differentiation, neuroplasticity, and neuroprotection and to show therapeutic effects in animal models of depression, stroke, drug abuse, and neurodegenerative disorders. Its role in protein folding and degradation in the ER was reported in a 2007 paper.2 Cutamesine, an experimental Sig-1R agonist drug that has completed phase II clinical trials in major depression and post stroke recovery has very recently been reported to regulate the secretion of brain-derived neurotrophic factor (BDNF), importantly involved in neurogenesis.1 In a time and dose-dependent manner, the drug potentiated the secretion of BDNF without affecting mRNA levels of BDNF. The researchers of paper #1 found that cutamesine potentiates the post-translational processing of neurotrophins. It decreased the intracellular level of pro-BDNF and mature BDNF while increasing the extracellular level of mature BDNF which the authors report to be a different mechanism than that of clinically used antidepressants that promote the upregulation of BDNF.

The researchers explain that BDNF is secreted after a complex process starting with a pre-proBDNF in the endoplasmic reticulum (ER) and then undergoing a series of steps involving glycosylation, sorting, proteolytic cleavage, and finally secretion.

By serendipity, we found a 2011 paper3 in our files that reports finding sigma-1 receptor stimulation by dehydroepiandrosterone (DHEA). The researchers report that “[w]e here found that sigma-1 receptor stimulation by DHEA improves cognitive function through phosphorylation of synaptic proteins in olfactory bulbectomized (OBX) mouse hippocampus.”3 They didn’t assess DHEA effects on BDNF in this study. The olfactory bulbectomized mouse is an animal model of depression which, in a previous study by these authors, resulted in impaired signaling of calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) in the OBX mouse hippocampus. Significant improvement resulted after treatment of the OBX mice with DHEA (30 or 60 mg/kg p.o. once a day) for 7–8 days after the OBX operation. Spatial, cognitive and conditioned fear memories were significantly improved as assessed by Y-maze, novel object recognition, and passive avoidance task, respectively. DHEA also improved impaired hippocampal long-term potentiation (a mechanism of learning) in the OBX mice.

The authors also cite papers by other groups that report finding that DHEA interacts with sigma-1R.

Although the researchers in their latest1 study did not evaluate changes in BDNF secretion in response to DHEA administration, it is interesting to note that the olfactory bulb is one of the two brain areas (in mice as well as in humans) that generates new neurons throughout life (via neurogenesis) in adult animals, a process in which BDNF is importantly involved.

Following up on this subject, we also found a 2001 paper4 that reported detailed studies of the interaction between neuroactive steroids, such as “pregnenolone, dehydroepiandrosterone, and their sulfate esters [that] behave as sigma-1 agonists, while progesterone is a potent antagonist.”4 More on sigma-1 receptor function was reported in this paper, including its modulation of intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and effects on monoaminergic systems. “Selective agonists of this recently cloned receptor [sigma-1] have potent anti-amnesic, anti-depressant, and anti-stress effects, while selective antagonists have antipsychotic and anti-addictive property.”4 Dehydroepiandrosterone is reported to exhibit anti-amnesic (memory enhancing) effects as a result of its interaction with the sigma-1 receptor.4 Higher levels of pregnenolone, another sigma-1 receptor agonist, was reported in two studies of aged rats to be correlated with learning ability and memory performances in a water maze and two-trial recognition task.

In another study described in the review paper4 a single systemic injection of DHEA sulfate immediately after training improved the impairment of memory in middle aged and old mice submitted to a footshock active avoidance test, “bringing it back to levels observed in young mice.” The authors of paper #4 also stated that “this neuroactive steroid [DHEA] plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems.”

References

  1. Fujimoto et al. Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse 66:630-9 (2012).
  2. Hayashi and Su. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596-610 (2007).
  3. Moriguchi et al. Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice. J Neurochem 117:879-91 (2011).
  4. Maurice et al. The interaction between neuroactive steroids and the sigma-1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev 37:116-32 (2001).

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