Somatostatin prevents lipopolysaccharide-induced neurodegeneration in the rat substantia nigra by inhibiting the activation of microglia

Abstract

Somatostatin (SST) is a neuromodulator which is abundant throughout the central nervous system (CNS) and has a crucial role in neurodegenerative disorders. However, little is known about the effects and mechanisms of SST in dopaminergic (DA) neurons in the context of Parkinson’s disease (PD). In the present study, a model of PD was generated by injecting lipopolysaccharide (LPS) into the substantia nigra (SN) of rats in order to investigate the effects of SST on LPS-induced degeneration of DA in vivo. Intramural injection of LPS resulted in a significant loss of DA neurons, while reduction of neuronal death by SST pretreatment was confirmed using immunohistochemical staining for tyrosine hydroxylase and Nissl. In parallel, immunohistochemical detection of OX-42 and hydroethidine staining were employed to determine the activation of microglia and production of reactive oxygen species (ROS), respectively. It was found that SST inhibited the LPS-induced microglial activity and ROS production. ELISA revealed a decreased production of pro-inflammatory mediators, including tumor necrosis factor-α, interleukin-1β and prostaglandin E2 when SST was administered prior to LPS treatment. Western blot analysis showed that LPS-induced expression of inducible nitric oxide synthase, cyclooxygenase-2 and nuclear factor κB (NF-κB) p-p65 was attenuated by administration of SST prior to LPS application. The results indicated that LPS-induced loss of nigral DA neurons was inhibited by SST and the observed effects of SST on neuroprotection were associated with suppression of microglial activation and the NF-κB pathway, ensuing decreases of neuroinflammation and oxidative stress. The present study therefore suggested that SST is beneficial for treating neurodegenerative diseases, such as PD, through inhibiting the activation of microglia.

The Synergy of Aging and LPS Exposure in a Mouse Model of Parkinson’s Disease

“…In this study, intranasal instillation of LPS also induced PD model in both young and aged mice. Other studies showed that LPS resulted in a significant loss of DA neurons, accompanied by the activation of microglia and NF-kB pathway [ 51 , 52 ]. LPS also induced the formation of α-synuclein fibrils with distinct structures, supporting the concept that LPS may generate unique synuclein fibril strains, which then spread to the CNS, leading to distinct pathological phenotypes and perhaps to different synuclein-related diseases [ 53 ].…”

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

“…In this study, SST was also able to prevent neuronal cell death and to reduce production of TNF- α , IL-1 β , PGE 2 , and ROS by the substantia nigra [153], all of which are known to be produced by activated microglial cells in models of PD [154]. Therefore, it was suggested that protective effects of SST on neuronal survival in this model of PD are associated with its ability to reduce microglial activation.…”

“…In a recent study performed in a rat model of PD generated by injecting LPS into the brain's substantia nigra, SST pretreatment was able to dramatically decrease the number of activated microglial cells [153]. In this study, SST was also able to prevent neuronal cell death and to reduce production of TNF- α , IL-1 β , PGE 2 , and ROS by the substantia nigra [153], all of which are known to be produced by activated microglial cells in models of PD [154].…”

Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection-induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity

“…+ LPS (striatum) group. The data are presented as the mean ± SEM activation [46,47]. These results highlight the neuroprotective role of microglial immunocompetent restriction in neuroinflammation-induced neurodegenerative diseases.…”