The effects of chronic nitric oxide synthase suppression on glioma pathophysiology.

Nitric oxide synthase (NOS) is strongly expressed in glioma and has an important role in tumour blood flow (TBF) regulation. Whether manipulation of NOS function within a tumour can have any therapeutic effect is unknown. This study therefore evaluated the pathophysiological effects of chronic systemic NOS inhibition on experimental rodent glioma blood flow, growth and necrosis. To determine the duration and pathophysiological effects of systemic NOS inhibition, Ng-nitro-L-arginine methyl ester (L-NAME) was given to rats bearing C6 glioma acutely (single dose i.v., 30 mg kg) or for either 4 or 7 days (i.p. 75 mg kg day) prior to study. TBF and local cerebral blood flow (LCBF) were measured using C14-iodoantipyrine quantitative autoradiography. Tumour volume, tumoural necrosis and tumoural NOS were measured using conventional neuropathology and immunocytochemistry. Acute and 4-day L-NAME administration produced significant TBF reductions (-48 and -39%, respectively) with less marked changes in LCBF (-35 and -15%, respectively). Seven-day L-NAME administration reduced tumour volume (p = 0.12), increased tumoural necrosis (p < 0.05), but immunohistochemistry showed no difference in tumoural NOS expression. These results confirm that NOS has a significant role in the pathophysiology of experimental glioma, and that in this glioma model the effects of chronic systemic NOS inhibition are, for the period under study, predominately anti-tumoural. Whether chronic NOS inhibition is useful as an adjunct in glioma therapy or provides the opportunity for novel therapeutic approaches requires further study.

Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma.

C6 glioma strongly express nitric oxide synthase. Rats bearing C6 tumours were pre-treated with i.v. Ng-nitro-L-arginine methyl ester (L-NAME), 3-morpholinosydnonimine (SIN-1) or saline before local cerebral blood flow (LCBF) or tumour capillary permeability (TCP) was measured by the [14C]iodoantipyrine autoradiographic or [14C]alpha-amino-isobutyric acid techniques. L-NAME and SIN-1 caused significant TBF alterations (-44% and +136%, respectively) with less marked (-15% and +33%) alterations in normal brain. Calculated cerebrovascular resistance changes within tumour were indeed selective. Baseline TCP was increased compared with normal brain (20-fold). L-NAME and SIN-1 administration did not alter TCP. These effects have significant implications for human malignant glioma management. Selective i.v. manipulation of LCBF, without significant changes in TCP, could increase the efficacy of chemotherapy, radiotherapy or provide better peritumoural oedema control.

Effects of nitric oxide manipulation on the disposition of platinum in an experimental glioma model.

Rodents with striatal C6 glioma were given carboplatin (65 mg kg(-1) in a 10 mg ml(-1) solution, i.v.) after pretreatment with the NO modulating agents 3-morpholinosydnonimine (SIN-1), NG-nitro-L-arginine methyl ester (L-NAME), bradykinin or dexamethasone, to determine whether platinum disposition in the glioma and normal brain was altered. There was no significant change in mean glioma platinum disposition after 3 days of dexamethasone (32+/-9.7 microg/g). Treatment with SIN-1 (45.1+/-14.2 microg/g), L-NAME (42.9+/-4.9 microg/g) and bradykinin (45.7+/-11.3 microg/g) all resulted in increased tumour platinum concentration compared with controls (29+/-5.5 microg/g) but these results were not statistically significant. Dexamethasone significantly (p < 0.05) reduced the platinum concentration in normal brain but the other agents had no effect. Although glioma platinum concentration could be increased by some agents that alter tissue NO levels, the patterns of response were unpredictable and the magnitude (approximately 50%) of the increased platinum disposition is unlikely to be biologically significant.

Pineal apoplexy: an occurrence with no diagnostic clinicopathological features.

Symptomatic pineal apoplexy unlike pituitary apoplexy is uncommon. A patient with an apoplectic pineal cyst, identified preoperatively using MRI and confirmed histologically presented with episodic syncope, and features of raised intracranial pressure, but no localizing neuro-ophthalmological signs. This case prompted a review of the clinicopathological features of pineal apoplexy. There are no diagnostic clinical features and the neuropathological associations of pineal region haemorrhage are diverse. There is no consistent clinicopathological syndrome of pineal apoplexy.

Nitric oxide synthase activity in human glioblastoma : a histochemical study.

Nitric oxide (NO), which is synthesised by the enzyme Nitric Oxide Synthase (NOS), mediates many physiological and pathological mechanisms in the brain. Experimental studies of rodent C6 glioma show that NO has a major role in regulation of tumour blood flow. To determine the relevance of these findings to human malignant glioma, NADPH diaphorase (NADPHd) histochemistry, which is a marker for NOS expression, was performed in 20 glioblastomas. Except for one tumour which was totally necrotic, all the 19 tumour specimens showed evidence of NADPHd expression. The neoplastic vascular endothelium, areas of endothelial proliferation and neoplastic astrocytes all consistently showed high levels of NADPHd positivity. Areas of necrotic tumour were always NADPHd negative. Both the extent and the intensity of cellular staining within the glioblastoma was considerably greater than NADPHd positivity in normal brain tissue. These results together with findings in experimental glioma strongly suggest that NOS has a definite role in the pathophysiology of glioblastoma and that it may be possible to pharmacologically manipulate them for therapeutic benefit.

Exophytic pontine glioblastoma mimicking acoustic neuroma.

A 22-year-old male with unilateral facial, cochlear and glossopharyngeal cranial nerve dysfunction and ataxia that was slowly progressive over one year is described. Although clinically it was considered he probably had an acoustic neuroma, surgery revealed a pontine glioblastoma exophytic into the cerebellopontine angle and internal acoustic meatus. Clinicoradiological features that distinguish this extremely rare lesion of the hindbrain from acoustic neuroma are discussed.