Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

Abstract

The cholinergic system plays a crucial role in modulating in the central nervous system physiological responses such as neurogenesis, neuronal differentiation, synaptic plasticity, and neuroprotection. In a recent study, we showed that Oxotremorine-M, a non-selective muscarinic acetylcholine receptor agonist, is able to transactivate the fibroblast growth factor receptor and to produce a significant increase in the hippocampal primary neurite outgrowth. In the present study we aimed to explore in the rat hippocampus the possible effect of acute or chronic treatment with Oxotremorine-M on some heat shock proteins (Hsp60, Hsp70, Hsp90) and on activation of related transcription factor heat shock factor 1 (HSF1). Following single injection of Oxotremorine-M (0.4 mg/kg) all Hsps examined were significantly increased in at least one of the time points studied (24, 48, and 72 hr). Treatment with Oxotremorine-M significantly increased the level of phosphorylated HSF1 in all time points studied, without change of protein levels. Similar pattern of Hsps changes was obtained following chronic Oxotremorine-M treatment (0.2 mg/kg) for 5 days. Surprisingly, following chronic treatment for 10 days no changes were observed in Hsps. The muscarinic acetylcholine receptor antagonist scopolamine (1 mg/kg) was able to completely block Oxotremorine-M effects on Hsps. In conclusion, considering the function of Hsps in protecting neuronal cells from deleterious proteotoxic stress, for example, protein mis-folding and aggregation, the results obtained indicate that muscarinic acetylcholine receptor activation may have implications in potential treatment of neurodegenerative disorders linked to protein aggregation, such as Alzheimer disease.

Differential expression of acetylcholinesterase 1 in response to various stress factors in honey bee workers

“…Considering that HSF1 is specific for hsp transcription, activation of Amace1 may not be directly regulated by HSR but rather by the upstream kinase pathways. Considering that Hsp expression is regulated by mAChR activation in the rat hippocampus 56 and AmAChE1 regulates the ACh titer, perhaps by sequestration, AmAChE1 likely exerts its functions via the mAChR-mediated pathway in the honey bee as well. If this is the case, as the cAMP-dependent protein kinase (PKA) pathway is known to activate HSF1 55 , AmAChE1 appears to exert its function via the PKA pathway mediated by mAChR, thereby modulating the stress response.…”

Anti-inflammatory and antioxidant effects of muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

“…1A. The Oxo dose of 0.4 mg/kg for acute treatment has been chosen in relation to our previous experience 9 . Oxo and scopolamine were dissolved in 0.9% physiological saline solution before use and the scheduled dose was given intraperitoneally (i.p.)…”

“…in a volume of 0.5 ml, as well as vehicle saline treatment. For chronic Oxo treatment we used the dose of 0.2 mg/Kg instead of that used for acute treatment, both in relation to our previous experience 7,9 and literature data 17,92 and to previous preliminary test, in which the chronic treatment with the dose of 0.2 mg/Kg was better tolerated by the animals compared to 0.4 mg/kg.…”

“…More recently, we evidenced that Oxo treatment recovered rats from the stress-induced anxiety-like behavior, and restored fibroblast growth factor 2 (FGF2) and brain derived neurotrophic factor (BDNF) levels in ventral hippocampus and prefrontal cortex 7 , two brain regions considered responsible of chronic restraint stress (CRS) induced anxiety. In another work, we found that Oxo up-regulates heat shock proteins and activates their transcription factor heat shock factor 1 (HSF1) in the rat hippocampus 9 . Heat shock proteins, in addition to their importance in protecting neurons from protein mis-folding and aggregation, are also regulators of inflammation and oxidative stress 10 .…”

Heat shock protein 60 and cardiovascular diseases: An intricate love‐hate story

“…52 Among the possible neurological pathways mediating the expression of HSPs, it has been determined that cholinergic activation via muscarinic acetylcholine receptors in hippocampal neurons leads to an increase in heat shock transcription factor 1 (HSF1)-Ser326 modification which leads to the activation of this transcription factor, with a dose and time-dependent increase in HSPs including HSP70, HSP90, and HSP60. 53 In various types of cancer, HSP60 appears to have a role in diagnosis, prognosis and prevention. [54][55][56][57] Different cancers present increased levels of HSP60 and seems to be linked to prosurvival mechanisms, such as uncontrolled proliferation and loss of replicative senescence.…”