Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation

Abstract

Depression is one of the common non-motor symptoms of Parkinson’s disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this study, we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model. Mice were administered reserpine (3 μg/mL in the drinking water) for 10 weeks. From the 10th week, BoNT/A (10 U·kg−1·d−1) was injected into the cheek for 3 consecutive days. We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta (SNpc) and striatum. BoNT/A treatment significantly ameliorated the depressive-like behaviors, but did not improve TH activity in SNpc of reserpine-treated mice. We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region. Furthermore, BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses, thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice. Moreover, BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-α and IL-1β in reserpine-treated mice. In addition, we showed that BoNT/A (0.1 U/mL) ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro. We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses.

The complement system: a potential target for the comorbidity of chronic pain and depression

“…This treatment resulted in the restoration of synaptic density, as evidenced by the increased co-localization of the excitatory presynaptic vesicle protein vesicular glutamate transporter-2 (VGLut2) with PSD-95, and the decreased fluorescence co-localization of VGlut2 with Iba-1 and CD68, indicating a reduction in microglial phagocytic activity. Furthermore, the expression of pro-inflammatory factors, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in microglial cells decreased, indicating the inhibitory effect of BonT/A on the C1q-C3/CR3-mediated complement cascade signaling pathway in the hippocampal CA1 region and subsequent alleviation of depression in Parkinson's mice [ 49 ]. In mouse models of visceral chronic pain induced by chronic stress, there was a significant increase in the expression levels of complement C1q and integrin alpha M (ITGAM) mRNA (which encodes the CD11b subunit of CR3) within amygdala microglial cells.…”

“…Notably, the absence of the C1q gene impeded the synaptic loss and depressive behaviors induced by CRS in mice, thereby illuminating the significant involvement of C1q/C3mediated microglial activation and synaptic pruning in the mechanisms underlying the onset of depression [48]. This was observed specifically in the hippocampal CA1 [49]. In mouse models of visceral chronic pain induced by chronic stress, there was a significant increase in the expression levels of complement C1q and integrin alpha M (ITGAM) mRNA (which encodes the CD11b subunit of CR3) within amygdala microglial cells.…”

“…The expression of PFC C3 increased significantly in depressed suicide patients. Chronic stress leads to increased C3 expression in PFC [20] CUMS mice [20] Depression C1q/C3 Neuroinflammation was observed in the glial cells, of the amygdala, C1q and C3 activation, Syn and PSD-95 levels decreased [48] CRS mice [48] Chronic pain and depression C1q/C3-CR3 BoNT/A treatment decreased the levels of complement C3\CR3 and C1q, decreased the colocalization of iba-1 and CD68, decrease the mRNA expression of CX3CR1 in microglia cells, recovered the density of PSD-95, decreased the mRNA levels of TNF-α and IL-1β [49] PD mouse model, Mice were administered reserpine (3 μg/ mL in the drinking water) for 10 wk. BoNT/A (10 U•kg-1•d-1) was injected into the cheek for 3 consecutive days [49] Chronic pain and depression…”

Ethanolic Extract of <i>Alternanthera Sessilis</i>: A Potential Therapeutic Agent for Behavioral Improvements in Reserpine-Induced Parkinsonian Rats

“…This creates a model that slowly develops both movement and non-movement problems, similar to how PD progresses in humans. [5,6] Reserpine depletes key brain chemicals, causing oxidative stress and inflammation, and triggers processes that damage nerve cells. It also reduces an enzyme needed for dopamine production, increases a protein linked to PD, and makes brain cells more sensitive to dopamine.…”