Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1–42-Injected, Wild-Type Mouse Model of AD

Abstract

Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore, S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine (DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and anti-neuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high affinity to 5-HT receptors, negatively influenced neurogenesis, possibly as a result of activating both receptors differently. In contrast, the highly selective S1R agonist PRE084 stimulated hippocampal cell proliferation and differentiation. Regarding neuroinflammation, DMT and PRE084 significantly reduced Aβ1-42-induced astrogliosis, but neither had remarkable effects on microglial activation. In summary, the highly selective S1R agonist PRE084 may be a promising therapeutic agent for AD. Further studies are required to clarify the multifaceted neurogenic and anti-neuroinflammatory roles of these agonists.

Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review

“…The oral LD 50 of DMT in mice was reported as 47 mg/kg intraperitoneally and 32 mg/kg intravenously. 49 A study conducted by Borbély and colleagues 50 investigated the neurogenic and anti-neuroinflammatory effects of DMT in a mouse model of Alzheimer's disease. DMT was intraperitoneally injected at a concentration of 1 mg/kg-1 into male C57BL/6 wild-type mice (n = 80), treated with either amyloid-β peptide 1-42-oligomers (polymer whose molecules consist of relatively few repeating units) or vehicle (phosphate-buffered saline [PBS]) as a control.…”

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

“…It is thought that this damage in the hippocampus can occur up to 10 years before cognitive symptoms appear in the patient. Studies using Aβ 1–42 [ 391 ] or Aβ 25–35 [ 392 ] injections into mouse brains have shown reduced proliferation and neurite growth, increased death of newly formed cells and an increase in the number of immature cells in mice brains. PRE-084 treatment promotes neurogenesis in mice treated with Aβ 1–42 or Aβ 25–35 [ 391 , 392 ].…”

“…Studies using Aβ 1–42 [ 391 ] or Aβ 25–35 [ 392 ] injections into mouse brains have shown reduced proliferation and neurite growth, increased death of newly formed cells and an increase in the number of immature cells in mice brains. PRE-084 treatment promotes neurogenesis in mice treated with Aβ 1–42 or Aβ 25–35 [ 391 , 392 ]. Furthermore, the density of hyper-reactive astrocytes was reduced by the administration of PRE-084 [ 391 ], suggesting PRE-084 may play an anti-inflammatory role.…”

“…PRE-084 treatment promotes neurogenesis in mice treated with Aβ 1–42 or Aβ 25–35 [ 391 , 392 ]. Furthermore, the density of hyper-reactive astrocytes was reduced by the administration of PRE-084 [ 391 ], suggesting PRE-084 may play an anti-inflammatory role. PRE-084 could also increase mushroom dendritic spine formation in the hippocampus of transgenic rats expressing presenilin-1 (PS1) and human APP (Swe) [ 393 ].…”

The past and present of therapeutic strategy for Alzheimer’s diseases: potential for stem cell therapy

“…PSEN1 FAD mutation knock-in mice show impaired adult neurogenesis associated with cognitive dysfunction and NPS status [100]. An increase in adult neurogenesis contributes to the improvement of cognitive dysfunction in AD model mice [101][102][103][104]. Therefore, adult neurogenesis in the hippocampus is an important target for AD therapy [105].…”