The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment

Abstract

Background Cerebral infection with the protozoan Toxoplasma gondii (T. gondii) is responsible for inflammation of the central nervous system (CNS) contributing to subtle neuronal alterations. Albeit essential for brain parasite control, continuous microglia activation and recruitment of peripheral immune cells entail distinct neuronal impairment upon infection-induced neuroinflammation. PACAP is an endogenous neuropeptide known to inhibit inflammation and promote neuronal survival. Since PACAP is actively transported into the CNS, we aimed to assess the impact of PACAP on the T. gondii-induced neuroinflammation and subsequent effects on neuronal homeostasis. Methods Exogenous PACAP was administered intraperitoneally in the chronic stage of T. gondii infection, and brains were isolated for histopathological analysis and determination of pathogen levels. Immune cells from the brain, blood, and spleen were analyzed by flow cytometry, and the further production of inflammatory mediators was investigated by intracellular protein staining as well as expression levels by RT-qPCR. Neuronal and synaptic alterations were assessed on the transcriptional and protein level, focusing on neurotrophins, neurotrophin-receptors and signature synaptic markers. Results Here, we reveal that PACAP administration reduced the inflammatory foci and the number of apoptotic cells in the brain parenchyma and restrained the activation of microglia and recruitment of monocytes. The neuropeptide reduced the expression of inflammatory mediators such as IFN-γ, IL-6, iNOS, and IL-1β. Moreover, PACAP diminished IFN-γ production by recruited CD4+ T cells in the CNS. Importantly, PACAP promoted neuronal health via increased expression of the neurotrophin BDNF and reduction of p75NTR, a receptor related to neuronal cell death. In addition, PACAP administration was associated with increased expression of transporters involved in glutamatergic and GABAergic signaling that are particularly affected during cerebral toxoplasmosis. Conclusions Together, our findings unravel the beneficial effects of exogenous PACAP treatment upon infection-induced neuroinflammation, highlighting the potential implication of neuropeptides to promote neuronal survival and minimize synaptic prejudice.

Effect of pituitary adenylate cyclase-activating polypeptide supplementation, applied during or after vitrification on mouse embryo

“…In two of these (EM 1 and EM 2), the treatment was carried out during the preparation for vitrification, when the Equilibration Medium was supplemented with 1 or 2 μM PACAP1-38. The full-length 38-amino acid peptide (PACAP-38) was synthesized at the Department of Medical Chemistry of the University of Szeged (Hungary) as described previously (Figueiredo et al, 2022). After thawing, the embryos were cultured for 24 h in CM without any supplementation.…”

Exosome-sheathed ROS-responsive nanogel to improve targeted therapy in perimenopausal depression

“…PACAP demonstrates a high affinity for its receptor, PAC1, which facilitates the execution of additional functions within the central nervous system (CNS). As a neuromodulator, neurotrophic factor, or neurotransmitter, PACAP is involved in pleiotropic functions in CNS, such as promoting neurogenesis [ 20 , 21 ], enhancing the development of hypersensitivity responses [ 22 ], anti-infection [ 23 , 24 ], inhibiting neuroinflammation [ 25 ], and regulating certain stress responses [ 26 – 28 ]. Despite this, the exact mechanisms underlying PACAP’s influence on depression and its potential therapeutic effects remain largely undiscovered.…”

Exosome-sheathed ROS-responsive nanogel as a novel drug carrier for targeted therapy of perimenopausal depression

“…PACAP demonstrates a high a nity for its receptor, PAC1, which facilitates the execution of additional functions within the central nervous system (CNS). As a neuromodulator, neurotrophic factor, or neurotransmitter, PACAP is involved in pleiotropic functions in CNS, such as promoting neurogenesis [17,18], enhancing the development of hypersensitivity responses [19], anti-infection [20,21], inhibiting neuroin ammation [22], and regulating certain stress responses [23][24][25]. Despite this, the exact mechanisms underlying PACAP's in uence on depression and its potential therapeutic effects remain largely undiscovered.…”