Journal of Neurological Sciences 155 (1998) 196–203 The expression of nitric oxide synthases in human brain tumours and peritumoral areas a b b, a c * A. Bakshi , T.C. Nag , S. Wadhwa , A.K. Mahapatra , C. Sarkar a Department of Neurosurgery, C.N. Centre, All India Institute of Medical Sciences, New Delhi, India b Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India c Department of Pathology, All India Institute of Medical Sciences, New Delhi, India Received 5 May 1997; received in revised form 27 August 1997; accepted 3 September 1997 Abstract Nitric oxide, a potent signalling molecule produced from L-arginine by nitric oxide synthase (NOS), has been implicated in diverse pathophysiological processes. Many characteristics of malignant tumours such as increased vascular permeability, vasodilation, neovascularisation and free radical injury to the tumour and adjacent normal tissues are believed to be mediated by nitric oxide. While NOS expression has been demonstrated in brain tumours, no equivalent studies have yet been reported on the adjacent peritumoral brain region. The present study examined the pattern of NOS expression in the human tumour and peritumoral brain areas. Biopsies were obtained from eight patients (six gliomas, one each of meningioma and metastatic adenocarcinoma) from three areas: tumour, peritumoral, and apparently ‘normal’ adjacent brain tissue. Immunohistochemical staining was performed for three isoforms of NOS: brain NOS (BNOS), endothelial NOS (ENOS) and macrophage-specific NOS (MacNOS). Except for glioblastoma multiforme and metastatic adenocarcinoma, the tumour cells expressed all three NOS isoforms. In four tumours, there was a demonstrable gradient of ENOS expression falling away from the tumour. In three gliomas, many glial cells were intensely labelled with BNOS. This labelling decreased in the peritumoral tissues. In four tumours, cells (presumably lymphocytes, and CD 45 positive macrophages) were labelled intensely with MacNOS in and around the blood vessels. These results suggest that nitric oxide is produced in the tumour cells and endothelium of tumour vasculature, while occasionally glial cells may also be induced to produce it. The possible role of nitric oxide in the production of peritumoral oedema is discussed.  1998 Elsevier Science B.V. Keywords: Brain tumour; Endothelium; Nitric oxide synthases; Oedema; Peritumoral brain 1. Introduction intrinsic capillary abnormalities it is likely that the per- meability of tumour capillaries is further increased by Peritumoral brain oedema (PBO) plays an important role immunological activity, tumour-related permeability fac- in the pathophysiology and clinical profiles of brain tors and inflammatory mechanisms (Baethman et al., 1980; tumours. The phenomenon varies with the tumour type and Del Maestro et al., 1984). is more a problem with malignant gliomas, metastatic The possible role of biochemical factors in the patho- carcinomas and meningiomas than with well-differentiated genesis of vasogenic brain oedema has been the subject of astrocytomas or oligodendrogliomas (Ito et al., 1986). considerable research. Tissue destruction, vascular throm- PBO is thought to be associated with the disruption of the bosis, ischemia, and immunological and inflammatory blood–brain barrier and increased vascular permeability reactions are characteristic histopathological features of (Brightman and Broadwell, 1976; Reichhman et al., 1986; many brain tumours. Therefore, a wide range of com- Kimelberg, 1995). PBO is primarily vasogenic and due to pounds generated by these processes could secondarily potentiate oedema formation (Baethman et al., 1980; Del * Corresponding author. Tel.: 191 11 6594875; fax: 191 11 6862663. Maestro et al., 1984). Oxygen free radicals, such as 0022-510X / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII S0022-510X(97)00315-8