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Published on: November 20, 2015
VU0360172 exerts anti-inflammatory effect on germinal matrix hemorrhage in neonatal rats via the mGluR5/PI3Kγ/PPARγ
Xiaoya Wang1, Jianwei Xu2, Ying Liu3
1The Medical Function Laboratory of Experimental Teaching Center of Basic Medicine, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China.
Background:
This study investigated the neuroprotective and anti-inflammatory effects of the mGluR5-specific positive allosteric modulator VU0360172 on germinal matrix hemorrhage (GMH) in neonatal rats, as well as the pharmacological mechanism pathway that may underlie this anti-inflammatory effect.
Methods:
A GMH model was established by intracerebral injection of 0.3 U collagenase VII-S in 7-day-old Sprague-Dawley rats. Animals were randomly divided into the following seven groups: (1) Sham, (2) GMH, (3) GMH +VU0360712 (0.75 mg/kg), (4) GMH + VU0360712 (1.5 mg/kg), (5) GMH + VU0360712 (3.0 mg/kg), (6) GMH + VU0360172 (3.0 mg/kg) + MTEP (0.6 mg/kg), and (7) GMH + VU0360172 (3.0 mg/kg) + AS-605240 (1.8 mg/kg). Western blot analysis was conducted on samples collected at 0, 3, 12 and 24 h and 3 and 7 days post-surgery to observe the postoperative changes in metabotropic glutamate receptor 5 (mGluR5). The neuroprotective and anti-inflammatory effects of different doses of VU0360172 (0.75, 1.5, and 3.0 mg/kg) on GMH were evaluated through neurological behavior testing, brain water content, brain hemorrhage volume, hematoxylin and eosin staining, and ELISA. Finally, MTEP and AS-605240 as inhibitors, were administered to explore the inflammatory regulation and microglial polarization regulation of the mGluR5/PI3Kγ/PPARγ pathway.
Results:
The results demonstrated that mGluR5 levels started to decline as early as 3 hours after GMH and reached a minimum at 24 hours. Compared with the GMH group, treatment with VU0360172 reduced improved neurological deficits, brain edema, and hemorrhage, reduced tissue loss and inflammatory cell infiltration, and alleviated the inflammatory response, with the middle and high doses showing particularly notable effects (P < 0.05). However, both MTEP and AS-605240 reversed the regulatory effects of VU0360172 on the mGluR5/PI3Kγ/PPARγ pathway. Significant reversals in the expression of key inflammatory factors and microglial markers were observed in the MTEP and AS-605240 groups compared to the high-dose VU0360172 group (P < 0.05).
Conclusion:
VU3060172 has a neuroprotective effect and anti-inflammatory properties on the GMH mouse model. Its anti-inflammatory mechanism may be achieved by activating the mGluR5/PI3Kγ/PPARγ pathway to regulate microglial polarization.
Insights
The drug VU0360172 demonstrates neuroprotective and anti-inflammatory benefits in a neonatal rat model of germinal matrix hemorrhage (GMH). Its mechanism involves activating the mGluR5/PI3Kγ/PPARγ pathway, influencing microglial polarization to reduce inflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Inflammation Research
Background:
- Germinal matrix hemorrhage (GMH) is a significant cause of brain injury in neonates.
- Understanding the neuroprotective and anti-inflammatory mechanisms in GMH is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the neuroprotective and anti-inflammatory effects of VU0360172, a positive allosteric modulator of mGluR5.
- To elucidate the underlying pharmacological pathway, specifically the role of the mGluR5/PI3Kγ/PPARγ pathway in mediating these effects.
Main Methods:
- A collagenase-induced GMH model was established in neonatal Sprague-Dawley rats.
- Different doses of VU0360172 were administered, along with inhibitors MTEP and AS-605240, to assess its effects.
- Neurobehavioral tests, brain water content, hemorrhage volume, histological analysis, and Western blot were used to evaluate outcomes and pathway activation.
Main Results:
- VU0360172 treatment significantly improved neurological deficits, reduced brain edema, hemorrhage, and inflammatory cell infiltration in the GMH model.
- The drug demonstrated dose-dependent effects, with middle and high doses showing notable improvements.
- Inhibitors MTEP and AS-605240 reversed the beneficial effects of VU0360172, indicating the involvement of the mGluR5/PI3Kγ/PPARγ pathway.
Conclusions:
- VU0360172 exhibits significant neuroprotective and anti-inflammatory properties in a neonatal rat model of GMH.
- The anti-inflammatory mechanism is associated with the activation of the mGluR5/PI3Kγ/PPARγ pathway, which regulates microglial polarization.
