Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer's Disease APP/PS1 Mouse Model

Abstract

Sigma-1 receptor agonists have recently gained a great deal of interest due to their anti-amnesic, neuroprotective, and neurorestorative properties. Compounds such as PRE-084 or pridopidine (ACR16) are being studied as a potential treatment against cognitive decline associated with neurodegenerative disease, also to include Alzheimer’s disease. Here, we performed in vitro experiments using primary neuronal cell cultures from rats to evaluate the abilities of ACR16 and PRE-084 to induce new synapses and spines formation, analyzing the expression of the possible genes and proteins involved. We additionally examined their neuroprotective properties against neuronal death mediated by oxidative stress and excitotoxicity. Both ACR16 and PRE-084 exhibited a concentration-dependent neuroprotective effect against NMDA- and H2O2-related toxicity, in addition to promoting the formation of new synapses and dendritic spines. However, only ACR16 generated dendritic spines involved in new synapse establishment, maintaining a more expanded activation of MAPK/ERK and PI3K/Akt signaling cascades. Consequently, ACR16 was also evaluated in vivo, and a dose of 1.5 mg/kg/day was administered intraperitoneally in APP/PS1 mice before performing the Morris water maze. ACR16 diminished the spatial learning and memory deficits observed in APP/PS1 transgenic mice via PI3K/Akt pathway activation. These data point to ACR16 as a pharmacological tool to prevent synapse loss and memory deficits associated with Alzheimer’s disease, due to its neuroprotective properties against oxidative stress and excitotoxicity, as well as the promotion of new synapses and spines through a mechanism that involves AKT and ERK signaling pathways.

Effect and mechanism of acupuncture on Alzheimer’s disease: A review

“…Acupuncture can reduce oxidative stress and reduce neuroinflammation through multiple signal transduction pathways, Aβ Production, aggregation, and phosphorylation of Tau. Beura et al, 2022;Estévez-Silva et al, 2022;Maina et al, 2022). We believe that abnormal mitochondria in susceptible neurons play a source role by providing diffusible hydrogen peroxide on the membrane to the surrounding cytoplasm, as shown in Figure 3.…”

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

“…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 ].…”

“…Pridopidine protects against NMDA-induced oxidative stress in primary hippocampal cultures and can increase mushroom dendritic spine formation in the hippocampus of transgenic rats expressing presenilin-1 (PS1) and human APP (Swe) , as well as reduce deficits in spatial learning [ 393 ]. The study also showed that pridopidine induced ERK and AKT phosphorylation.…”

“…The study also showed that pridopidine induced ERK and AKT phosphorylation. Thus, the involvement of the mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathways, through which the σ1R may control the neuroprotective properties and synaptogenesis [ 393 ].…”

Parapyruvate Induces Neurodegeneration in C57BL/6JNarl Mice via Inhibition of the α-Ketoglutarate Dehydrogenase Complex

“…Spatial learning and memory impairment are common behavioral indicators used to assess the neurodegeneration status in mice. − In our previous study, we performed the Morris water maze (MWM) test and active avoidance test to assess the effect of ergothioneine on the spatial learning and memory function in the C57BL/6JNarl mice . However, the effect of parapyruvate on inducing behavioral changes in the MWM and active avoidance tests is unknown.…”