Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system.

Recent evidence has shown that an increase in CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells may contribute to stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that stroke activates the sympathetic nervous system, which was abolished by 6-OHDA. The consequent activation of ß2-adrenergic receptor (AR) signaling increased prostaglandin E2 (PGE2) level in bone marrow. ß2-AR antagonist prevented the upregulation of PGE2. PGE2, which acts on prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-κB ligand (RANKL) in CD4(+) T cells and mediated the increase in Treg cells in bone marrow. Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells. PGE2 also elevated the expression of indoleamine 2,3 dioxygenase in CD11C(+) dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with indomethacin. Concurrently, stroke reduced production of stromal cell-derived factor-1 (SDF-1) via ß3-AR signals in bone marrow but increased the expression of C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with ß3-AR antagonist SR-59230A reduced the percent of Treg cells in peripheral blood after stroke. The disruption of the CXCR4-SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4(+) cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after stroke. We conclude that cerebral ischemia can increase bone marrow CD4(+)CD25(+)FoxP3(+) regulatory T cells via signals from the sympathetic nervous system.

Bone marrow mononuclear cells exert long-term neuroprotection in a rat model of ischemic stroke by promoting arteriogenesis and angiogenesis.

Transplanted bone marrow-derived mononuclear cells (BMMNCs) can promote arteriogenesis and angiogenesis by incorporating into vascular walls and differentiating into smooth muscle cells (SMCs) and endothelial cells (ECs). Here, we explored whether BMMNCs can enhance arteriogenesis and angiogenesis and promote long-term functional recovery in a rat model of permanent middle cerebral artery occlusion (pMCAO). Sprague-Dawley rats were injected with vehicle or 1×10(7) BMMNCs labeled with BrdU via femoral vein 24 h after induction of pMCAO. Functional deficits were assessed weekly through day 42 after pMCAO, and infarct volume was assessed on day 7. We visualized the angioarchitecture by latex perfusion on days 14 and 42. BMMNC transplantation significantly reduced infarct volume and neurologic functional deficits compared with untreated or vehicle-treated ischemic groups. In BMMNC-treated rats, BrdU-positive cells were widely distributed in the infarct boundary zone, were incorporated into vessel walls, and enhanced the growth of leptomeningeal anastomoses, the circle of Willis, and basilar arteries. BMMNCs were shown to differentiate into SMCs and ECs from day 14 after stroke and preserved vascular repair function for at least 6 weeks. Our data indicate that BMMNCs can significantly enhance arteriogenesis and angiogenesis, reduce infarct volume, and promote long-term functional recovery after pMCAO in rats.

Incidental finding of metastatic prostatic adenocarcinoma of cerebellopontine angle presenting as acoustic neuroma: A case report and review of literature.

INTRODUCTION: Brain metastases from carcinoma of prostate are rare and only few cases with brain metastases preceding the diagnosis of carcinoma of prostate have been reported in the literature. Lesions of brain metastasis from prostate cancer had a large variety of imaging presentations and it is very difficult to distinguish them from the other types of brain occupying lesions. We report one case of metastatic prostatic adenocarcinoma of cerebellopontine angle presenting as acoustic neuroma, as the first clinical evidence of metastatic carcinoma of the prostate. PRESENTATION OF CASE: The 57-year-old male presented to the neurology clinic complaining of dizziness accompanied by right tinnitus, he was proposed to be diagnosed with acoustic neuroma, and the tumor resection was performed later in our neurosurgery department. The postoperative histopathological and immunohistochemical (IHC) examinations revealed a cerebellar pontine angle metastatic adenocarcinoma, which was then confirmed as prostate cancer metastasis. The patient refused surgical castration and only agreed to conservative treatment. The patient's condition continued to deteriorate, and he died 12 months after the initial presentation. DISCUSSION: Brain metastasis is rare in prostate cancer, which accounts for only 0.2 % to 2 % of all brain metastases. Intracranial metastasis as the first clinical symptom of prostate cancer is extremely rare. In our article, we report the VIIIth and VIIth cranial nerves palsy for the first time, caused by brain metastases from prostate cancer, with symptoms similar to an acoustic neuroma. Prostate cancer most commonly spreads to the bones, including the skull, Cranial nerve palsy is caused by extensive invasion of the skull base. The serum PSA level is considered the most valuable tool to monitor the disease progression of patients with prostate cancer metastasis. A high PSA level significantly increases the tendency of prostate cancer to metastasize to the brain. A high Gleason score is believed to help determine the risk and likelihood of brain metastases in patients with prostatic carcinoma. CONCLUSION: In our case, we initially report the VIIIth and VIIth cranial nerve palsy, mimicking an acoustic neuroma, caused by metastatic prostate carcinoma. For early diagnosis, the prostate should not be neglected as a possible source of the metastases in male patients presenting with brain metastases. High prostate specific antigen (PSA) level and high Gleason score can be useful parameters for the prediction of brain metastasis from prostate cancer. The PSA should play a vital role in distinguishing metastatic prostate carcinoma in male patients.

Comparison of the therapeutic effects of bone marrow mononuclear cells and microglia for permanent cerebral ischemia.

In this study we transplanted bone marrow mononuclear cells (BM-MNCs) or microglia into rats that had undergone permanent cerebral ischemia and observed the distribution or morphology of transplanted cells in vivo. In addition, we compared the effects of BM-MNCs and microglia on infarct volume, brain water content, and functional outcome after permanent cerebral ischemia. BM-MNCs and microglia were obtained from femur and brain, respectively, of newborn rats. Adult rats were injected with vehicle or 3 million BM-MNCs or microglia via the tail vein 24h after permanent middle cerebral artery occlusion (pMCAO). The distribution or morphologic characteristics of transplanted BM-MNCs (double stained with BrdU/Cd34 or BrdU/CD45) and microglia (double stained with BrdU/Iba-1) were detected with immunofluorescent staining at 3 or 7 and 14 days after pMCAO. Functional deficits were assessed by the modified neurologic severity score at 1, 3, 7 and 14 days after pMCAO. Brain water content was assessed at 3 days, and infarct volume was determined at 14 days. We observed more BrdU/CD45 and BrdU/Iba-1 double-stained cells than BrdU/CD34 double-stained cells around the infarcted area. Some infused microglia showed the morphology of innate microglia at 7 days after pMCAO, and the number increased at 14 days. BM-MNC-treated rats showed significantly reduced infarct volume and brain water content compared to vehicle- and microglia-treated rats. In addition, BM-MNC treatment reduced neurologic deficit scores compared to those in the other groups. The results provide evidence that infusion of BM-MNCs, but not microglia, is neuroprotective after permanent cerebral ischemia.