[Clinical features of 123 patients with hyperinsulinemic hypoglycemia auxiliarily diagnosed by 18F-DOPA-PET CT scanning].

Objective: To summarize the clinical features and therapeutic outcomes of patients with hyperinsulinemic hypoglycemia (HH) auxiliarily diagnosed by 18F-DOPA positron emission tomography (PET) CT scanning. Methods: The clinical data of 123 patients who were diagnosed with hyperinsulinemic hypoglycemia by comprehensive clinical diagnostic procedures in the Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University between January 2016 and December 2020 were retrospectively analyzed. Clinical data such as gender, age of onset, province, concurrent serum insulin level measured during hypoglycemia, lesion type of pancreas by 18F-DOPA-PET CT scanning, genetic test results, and treatment were collected successively. The clinical features and therapeutic outcomes were compared between patients with focal and diffuse pancreatic lesions. T test, Rank sum test, and χ² test were used for comparison between groups. Results: A total of 123 patients with hyperinsulinemic hypoglycemia (72 males and 51 females), whose average age of onset was 3 days (ranging from 1 day to 4 860 days), were recruited from 24 provinces. The concurrent serum insulin level was 7.1 (0.4-303.0) mU/L during hypoglycemia. 18F-DOPA-PET CT scanning identified focal lesions in 25.2% (31/123) and diffuse lesions in 74.8% (92/123) of the patients; 64.2% (79/123) of the HH cases were found to have pathogenic gene variants, in which 88.6% (70/79) were found to have KATP channel related genes (61 in ABCC8 and 9 in KCNJ11 mutations). Thirty-seven patients (17 focal and 20 diffuse) received surgical treatment with a success rate of 67.6% (25/37). The effective rate of diazoxide for children with diffuse type was significantly higher than that of children with focal group (28.3% (26/92) vs. 9.7% (3/31), χ²=10.31, P=0.001). Conclusions: 18F-DOPA-PET CT scan can improve the success rate of surgery. Comprehensive diagnosis of the etiology of hyperinsulinemic hypoglycemia by genetic analysis and 18F-DOPA-PET CT scanning can result in better treatment and prognosis.

Effects of YM872 on atrophy of substantia nigra reticulata after focal ischemia in rats.

Middle cerebral artery (MCA) occlusion causes atrophy in the ipsilateral substantia nigra reticulata (SNR). The effects of glutamate AMPA receptor antagonism on SNR atrophy, which is supposed to inhibit excitatory inputs from the subthalamic nucleus to the SNR, was investigated in rats with permanent MCA occlusions. Histological examination revealed marked atrophy two weeks after MCA occlusion in the saline-treated control group. However, constant i.v. infusion of YM872, a selective AMPA receptor antagonist, for 2 weeks significantly reduced SNR atrophy; neurological deficits also decreased. These results suggest that the AMPA receptor may be involved in the pathogenesis of SNR atrophy during the subacute phase of focal cerebral ischemia.

Neuroprotective efficacy of YM872, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, after permanent middle cerebral artery occlusion in rats.

The neuroprotective efficacy of YM872, a novel, highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, was investigated in rats subjected to permanent occlusion of the left middle cerebral artery. The rats were assessed either histologically or neurologically 24 hr or 1 wk after ischemia. YM872 was intravenously infused for either 4 or 24 hr at dose rates of 0 to 20 mg/kg/hr starting 5 min after ischemia to examine the effect of prolonged treatment. YM872 was then infused at 20 mg/kg/hr beginning 0 to 4 hr after ischemia to determine the efficacy time window. Additionally, a 20 mg/kg/hr dose rate of YM872 was infused for 4 hr in single day- or 5-day repetitive-administrations to evaluate long-term benefits of the drug. YM872 significantly reduced infarct volume in both 4- and 24-hr treatment groups measured 24 hr after ischemia. No difference was observed in the degree of protection between length of infusion. Significant neuroprotection was maintained even when drug administration was delayed up to 2 hr after ischemia. A single YM872-administration significantly improved neurological deficit and reduced infarct volume (30%, P <.01) measured 1 wk after ischemia. YM872 treatment did not induce such adverse effects as physiological changes, serious behavioral abnormalities or nephrotoxicity. These data suggest that the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor plays a crucial role in the progression of neuronal damage in the early phase of ischemia and that YM872 may be useful in treating acute ischemic stroke.

YM872, a novel selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, reduces brain damage after permanent focal cerebral ischemia in cats.

YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3, 4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate), a selective, potent and highly water-soluble competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, was investigated for its neuroprotective effect against focal cerebral ischemia in halothane-anesthetized cats. Cats were subjected to permanent occlusion of the left middle cerebral artery for 6 h, then sacrificed and examined histologically. The electroencephalogram and cerebral blood flow were monitored. Intravenous infusion of YM872 starting 10 min after the onset of ischemia at a rate of 2 mg/kg/h for 6 h markedly reduced the volume of ischemic damage by 61% (from 2604 +/- 202 mm3 of the cerebral hemisphere in saline-treated cats to 1025 +/- 277 mm3 in YM872-treated cats; P < .01), as assessed in 12 stereotaxically determined coronal sections. No significant differences were observed between YM872- and saline-treated cats concerning physiological variables including brain temperature. No precipitation of YM872 in the kidney was seen in any YM872-treated animal. The present data further support the notion that the AMPA receptor plays an important role in the progression of focal ischemic damage in a gyrencephalic model. This evidence for the neuroprotective efficacy of YM872 suggests its therapeutic potential in the treatment of acute stroke in humans.

Permanent occlusion of bilateral internal carotid arteries produces cognitive deficits in two learning behavior tasks.

We investigated the effects of permanent bilateral occlusion of the internal carotid arteries (2ICAO) on the learning and memory performances in rats to evaluate the permanent 2ICAO rats as a model for vascular dementia. The learning and memory performance was tested by a step-through passive avoidance task and an 8-arm radial maze task. Permanent 2ICAO decreased cerebral blood flows in the cortex and hippocampus by 46.3 +/- 3.3 and 21.1 +/- 4.6%, respectively, when measured at 15 min after occlusion. In the passive avoidance task, the 2ICAO rats showed no impairment of learning or of memory retention when tested 1 h after learning trial, while they showed a shorter latency than sham-operated rats when tested 24 h after learning trial. In the radial maze learning task, the non-pretrained 2ICAO rats showed impairment. The pretrained 2ICAO rats had no deficit in the radial maze retention task but they showed impaired performance when a 3-min delay was interposed in the task. These results suggest that permanent 2ICAO is a useful animal model for studying vascular dementia.

Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat.

The neuronal damages and the changes in central acetylcholine (ACh) and choline (Ch) contents following permanent occlusion of bilateral common carotid arteries (2VO) of rats were investigated 1 and 4 months after the operation. Two types of neuronal damages were observed in the rats with permanent 2VO. The first type was the infarctions observed in the cerebral cortex and striatum. The infarction in the cortex and striatum was observed in 28.6 and 42.9% of the animals examined 1 month after permanent 2VO, respectively. These ratios did not change even when examined 4 months after permanent 2VO, suggesting that this type of neuronal damage is due to acute ischemic attacks. The second type was progressive neuronal damages observed in the hippocampus and white matter: the neuronal loss in the CA1 subfield appeared 4 months but not 1 month after permanent 2VO and the rarefaction of white matter which was observed 1 months after permanent 2VO and markedly increased 4 months after the operation. Moreover, ACh level significantly decreased in the striatum but not in the cortex, hippocampus or hypothalamus 1 month after permanent 2VO, while the ACh levels in the cortex, striatum and hypothalamus, and Ch levels in all the regions tested significantly decreased when tested 4 months after the operation. These changes did not accompany necrosis. These results suggest that the progressive neuronal degeneration and cholinergic dysfunction following the permanent 2VO are in part involved in chronic cerebral hypoperfusion-induced long-lasting cognition deficits in rats.

Tetramethylpyrazine improves spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries or scopolamine in rats.

Effects of tetramethylpyrazine (TMP), a major constituent of Ligusticum chuanxiong, on spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries (2VO) and scopolamine were investigated using 8-arm radial maze performance in rats. Permanent 2VO produced a severe learning deficit in non-pretrained rats. Daily administration of TMP (3-10 mg/kg, i.p.) from the 3rd day after permanent 2VO significantly improved the learning deficit. TMP did not influence the impairment of the retention task in the pretrained permanent 2VO rats, but it tended to reduce the number of errors elevated by 3-min delay interposition in these rats. In the scopolamine model, scopolamine (0.3 mg/kg, i.p.) significantly decreased the initial correct response and increased the number of errors. Single administration of TMP (1-3 mg/kg, i.p.) dose-dependently reversed the scopolamine-induced impairment of the maze performance. These results suggest that TMP has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.

Peony and its major constituent, paeoniflorin, improve radial maze performance impaired by scopolamine in rats.

A traditional Chinese medicine, Shimotsu-to has been shown to improve spatial working memory in rats. Shimotsu-to consists of four herbs, Japanese angelica root, cnidium rhizome, peony root, and rehmannia root. In the present study, the effects of aqueous extracts of each component herb on scopolamine (0.3 mg/kg)-induced spatial working memory disruption were examined using an eight-arm radical maze task in rats. Among the four component herbs, peony root extract (0.25 and 1 g dried herb/kg, PO) exhibited the most potent antagonizing effect on the scopolamine disruption of the choice accuracy. Japanese angelica root extract (1 g dried herb/kg, PO) also significantly attenuated the scopolamine disruption, whereas neither cnidium rhizome nor rehmannia root affected it. Paeoniflorin (0.01-1 mg/kg, PO), a major constituent of peony root, dose-dependently attenuated the scopolamine-induced impairment in the choice accuracy. Scopolamine (0.3 mg/kg, IP) significantly decreased the acetylcholine contents in the hippocampus, cortex, and striatum. Although paeoniflorin alone did not affect the acetylcholine contents, pretreatment with paeoniflorin significantly prevented the scopolamine-induced decrease in the acetylcholine content in the striatum, but not in the hippocampus or cortex. These data suggest that peony root mainly contributes to the cognitive enhancing effect of Shimotsu-to and that paeoniflorin may be one of the active constituents of peony root.

A kampo prescription, shimotsu-to, improves scopolamine-induced spatial cognitive deficits in rats.

The effect of a Kampo (traditional Chinese medicine) prescription, Shimotsu-to, on spatial cognitive deficits produced by scopolamine was examined using an eight-arm radial maze and a T-maze. Scopolamine (SCOP; 0.075-0.3 mg/kg, ip) dose-dependently disrupted the radial maze performance. Single doses of Shimotsu-to (0.5 and 1.0 g/kg, po) as well as physostigmine (0.15 and 0.3 mg/kg, ip) improved the SCOP (0.3 mg/kg)-induced performance deficits in a dose-dependent manner. Shimotsu-to administered for 1 week in drinking water (0.5 and 1.0 g/kg/day) also exhibited dose-dependent reversal of SCOP-induced impairments in the radial maze performance. The same treatment improved SCOP (0.2 mg/kg)-induced impairments in T-maze delayed alternation performance. These data clearly demonstrated the beneficial effects of Shimotsu-to on spatial cognition.