High-dose dietary supplementation of vitamin A induces brain-derived neurotrophic factor and nerve growth factor production in mice with simultaneous deficiency of vitamin A and zinc.

Marginal vitamin A and zinc (Zn) deficiency often co-exist in many populations. Vitamin A plays a trophic role in brain and is important for its development. We investigated effects of dietary supplementation of vitamin A on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) production in mice depleted for vitamin A and Zn. After 3 months' feeding with a low vitamin A and Zn (LVA-LZ) diet, mice were divided into two groups and replenished with either normal or high vitamin A with low Zn diet for an additional 2 months. Levels of BDNF and NGF were measured from extracts of hippocampus, cortex and cerebellum at the end of the third and fifth months. The LVA-LZ group tended to show decreased amounts of the BDNF and NGF, while animals supplemented with high vitamin A along with Zn deficiency had high BDNF and NGF concentrations. From these results, we conclude that vitamin A may increase BDNF and NGF levels.

Distinct effects of anterior pyriform cortex and the lateral hypothalamus lesions on protein intake in rats.

Several specific locations in brain, including pyriform cortex and hypothalamus, are associated with regulation of food intake. Although lesions of these locations significantly alter food intake, their involvement in the selection of macronutrients is not well characterized. In this study, we examined distinct effects of anterior pyriform cortex (APC) and lateral hypothalamus (LH) lesions on protein intake in rats. The APC or LH of male adult rats were lesioned by treatment with kainic acid, and the rats were then given free access to two kinds of casein diets containing high (60%) and low (5%) protein. Total energy content of these diets was kept constant by changing the carbohydrate content. Following the APC lesions, body weight and food intake decreased, but returned to control levels on day 13 and day 4, respectively. APC lesions did not change the ratio of protein intake. In contrast, LH lesions disturbed body weight gain and the selection of a high protein diet for at least two weeks, although food intake returned to control levels by day 2. Our results suggest that LH, but not APC, may play an important role in the selection of protein intake in rats.

Increased nerve growth factor by zinc supplementation with concurrent vitamin A deficiency does not improve memory performance in mice.

We investigated the effects of dietary supplementation of zinc (Zn) with or without vitamin A (Vit. A), to elucidate any cross activity between the two micronutrients, on memory and nerve growth factor (NGF) production in ddY male mice depleted for the two elements. After 3 mo-feeding with a Zn and Vit. A deficient (VAD) diet, mice were divided into three groups and replenished with normal Zn with VAD diet (NZ-VAD), high Zn with VAD diet (HZ-VAD) or normal Zn + normal Vit. A (NZ-NVA) for additional 2 mo. One more group was made and given the normal diet for the same period (Control group). Levels of NGF were measured from extracts of hippocampus, cerebellum and cortex at the end of the 3rd and 5th month. In addition, a radial arm maze task was performed at the end of the 5th month. The two Zn supplemented groups (NZ-VAD and HZ-VAD) tended to show high NGF concentration but memory was not improved. However, improved memory was observed in the NZ-NVA group. From these results we concluded that Zn may increase NGF; however, memory was improved only when Vit. A was sufficient.

Enhanced hippocampal acetylcholine release in nociceptin-receptor knockout mice.

Nociceptin (NOC), an endogenous ligand of the opioid receptor-like 1 receptor, is thought to be involved in learning and memory processes. Since acetylcholine (ACh) is involved in hippocampal function, and the hippocampus plays a critical role on the learning and memory function, hippocampal ACh release in NOC-receptor knockout mice was examined using an in vivo microdialysis method. The release of hippocampal ACh was largely increased in the knockout mice. Furthermore, in the knockout mice, an enhanced hippocampal theta rhythm, which is known to be linked to hippocampal memory function, was also observed. Immunohistochemically, in septum, co-existence of NOC receptor with cholinergic, but not with GABAergic neurons, was verified. The findings demonstrate that the NOC receptor is involved in hippocampal cholinergic function.

DHEAS improves learning and memory in aged SAMP8 mice but not in diabetic mice.

Dehydroepiandrosterone sulfate (DHEAS) has been reported to improve memory in aged animals and suggested as a treatment for age-related dementias. The SAMP8 mouse, a model of Alzheimer's disease, has an age-related impairment in learning and memory and an increase in brain levels of amyloid precursor protein (APP) and amyloid beta protein (Abeta). Male SAMP8 mice also have a decrease in testosterone, to which DHEA is a precursor. Diabetes has been suggested as a model of aging and to be linked to Alzheimer's disease. Diabetics can have memory deficits and lower DHEAS levels. Here, we examined the effects of chronic oral DHEAS on acquisition and retention for T-maze footshock avoidance in 12 mo male SAMP8 mice and in CD-1 mice with streptozocin-induced diabetes. Learning and memory were improved in aged SAMP8 mice, but not in CD-1 mice with streptozocin-induced diabetes. These findings suggest that DHEAS is more effective in reversing the cognitive impairments associated with overexpression of Abeta than with diabetes.

Lack of nociceptin receptor alters body temperature during resting period in mice.

The role of nociceptin (NOC) receptor on body core temperature (Tcore) control was examined using NOC receptor knockout mice. In homozygote NOC receptor-knockout, wild-type, and control C57BL/6J and 129/SV mice, Tcore was continuously recorded under 12:12 h light:dark (LD) and conditions of constant darkness (DD). The Tcore values during the resting period were higher in the NOC receptor-knockout mice than in both wild-type and control mice under both LD and DD conditions. Spontaneous activity during the resting period and plasma cortisol levels were not different between the NOC receptor-knockout and control mice. The findings herein indicate that the NOC receptor is involved in the control of Tcore during the resting period and is independent of light, physical activity and/or cortisol regulation.

Antibody to beta-amyloid protein increases acetylcholine in the hippocampus of 12 month SAMP8 male mice.

Amyloid beta protein (Abeta) is the primary constituent of plaque seen in Alzheimer's disease. Abeta is proposed to play an etiological role in Alzheimer's disease and to be a cause of the decrease in the level of acetylcholine in the hippocampus. The SAMP8 strain of mouse develops age-related increases in Abeta and deficits in learning and memory by 12 months of age. We examined in 12 month old SAMP8 mice the effects of giving antibody to Abeta by septal or intracerebroventricular (ICV) injection on acetylcholine levels in the hippocampus. Antibody to Abeta increased acetylcholine in the hippocampus over 100% after ICV injection and over 200% after septal injection. Injection of rabbit serum, antibody directed towards mouse IgG, or a blocking antibody directed towards human interleukin-1beta were without effect. These results suggest that antagonism of Abeta increases acetylcholine concentrations in the hippocampus, an area important for learning and memory.

Mechanisms of HIV type 1-induced cognitive impairment: evidence for hippocampal cholinergic involvement with overstimulation of the VIPergic system by the viral coat protein core.

HIV-1 is associated with a neuroAIDS syndrome that includes cognitive impairment. Several components of HIV-1 are capable of affecting cognition, but which of these is the major mediator is unknown. We injected into the lateral cerebral ventricle of mice HIV-1 pseudoviruses expressing the full viral genome with or without the viral coat glycoproteins, gp120/gp41. Only virus possessing gp120/gp41 induced defects in memory as assessed in an active avoidance T-maze footshock paradigm. By itself, gp120 also induced impairments that were reversed by hippocampal cholinergic stimulation. Paradoxically, low doses of gp120 could improve memory. Such low-dose, paradoxic improvement is a characteristic of substances that impair memory by overstimulating pathways that normally sustain memory. Consistent with this, a low, but not a high, dose of gp120 reversed memory impairment induced by overstimulation of the VIPergic system, a memory-sustaining pathway. Further characterization showed that two strains of gp120 (SF and MN) were equally effective at improving memory and that, unlike other actions of gp120, glycation was not required. We conclude that (1) the predominant cognitive-impairing component of HIV-1 is its viral coat glycoproteins, (2) gp120 impairs memory by overstimulating pathways that normally sustain memory, (3) the cognitive effect of gp120 is mediated by its protein core, and (4) gp120 likely impairs memory by affecting the cholinergic/VIPergic system.

Distribution and immune responses resulting from oral administration of D-limonene in rats.

We investigated the relationship between the absorptive pathway and the immune responses of the lung, particularly the phagocytic function of alveolar macrophages (Mphi) after oral administration of D-limonene in rats. D-Limonene was orally administered in oily solution with a stomach tube in thoracic duct-cannulated rats, and the lymphatic output of D-limonene was measured. D-Limonene levels reached a maximum in thoracic duct lymph and lung 3 h after its oral administration. It also significantly increased in bronchoalveolar lavage fluid (BALF) and alveolar Mphi, in which there was frequently a focal exudation of lipid droplets containing D-limonene into the alveolar cavity through alveolar capillary walls. Second, D-limonene orally given to rats (250, 500, 1,000 mg/kg/d) for 8 consecutive days resulted in a marked increase in both the number and the phagocytic activity of alveolar Mphi compared to the controls. BALF from rats dosed with D-limonene (1,000 mg/kg/d) enhanced the phagocytic activity of alveolar Mphi from control rats because the dose was prolonged. The activity of alveolar Mphi following in vitro incubation with D-limonene also increased in a dose-dependent manner. An oral administration of D-limonene enhanced the Con A-stimulated proliferation of splenocytes. These results suggest that D-limonene taken up from the thoracic duct lymph moves to the lung and directly activates the immune response of alveolar MO there, or indirectly activates it through activated lymphocytes.