Preliminary evidence that rivastigmine-induced inhibition of serum butyrylcholinesterase activity improves behavioral symptoms in Japanese patients with Alzheimer's disease.

AIM: To investigate whether the inhibitory rate of serum butyrylcholinesterase (BuChE) activity in Japanese patients with Alzheimer's disease is correlated with cognitive function, behavioral symptoms and caregiver burden. METHODS: A total of 61 patients with mild to moderately severe Alzheimer's disease who were not undergoing cholinesterase enzyme inhibitor/memantine combinatorial treatment received a rivastigmine (18 mg) patch for 24 weeks. The rate of inhibition of BuChE was correlated with scores obtained on cognitive (Mini-Mental State Examination), behavioral (the Japanese version of the modified Crichton Geriatric Behavioral Rating Scale [CGBRS] and Vitality Index [VI]) and burden (the Japanese version of Zarit Burden Inventory [ZBI]) scales; and the Clinical Global Impression of Change scale. RESULTS: The serum BuChE activity showed a significant decrease after 24 weeks compared with baseline (P < 0.001). Overall, significant effects were found in the Mini-Mental State Examination score, VI score and modified CGBRS score. We then divided patient groups into a high inhibitory rate (≥40%) group and a low inhibitory rate (<40%) group; there were significant improvements in the Mini-Mental State Examination score, VI score and modified CGBRS score in both groups. However, favorable results were seen in cooperation, restlessness and leisure on modified CGBRS subscales in the high inhibitory rate group (P < 0.001, P = 0.007, P < 0.001, respectively), and rehabilitation and other activities on VI subscales in the high inhibitory rate group (P = 0.005) compared with those in the low inhibitory rate group. CONCLUSIONS: Demonstrable significant improvements in behavioral symptoms, such as low cooperation, restlessness or low activities in patients with Alzheimer's disease, were achieved on inhibition of BuChE at a rate of 40% or more. Geriatr Gerontol Int 2017; 17: 1306-1312.

The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans.

We previously described a polymorphism in exon 4 of the gene encoding the heme biosynthetic pathway enzyme, coproporphyrinogen oxidase (CPOX4), which significantly modifies the effect of mercury exposure on urinary porphyrin excretion in humans. Here, we examined potential consequences of this polymorphism ("CPOX4") on performance within neurobehavioral domains, symptoms, and mood that are known to be affected by elemental mercury (Hg degrees ) exposure in human subjects. A behavioral test battery was administered on the day of urine and buccal cell collections for 194 male dentists (DDs) and 233 female dental assistants (DAs) occupationally exposed to Hg degrees for an average of 19 and 10 years, respectively. Subjects had no history of health disorders and were employed for a minimum of 5 years in the dental profession. Respective mean urinary mercury (HgU) levels in DDs and DAs were 3.32 (4.87) microg/l and 1.98 (2.29) microg/l. Corresponding indices of chronic occupational Hg degrees exposure, weighted for historical exposure, were 27.1 (20.6) and 15.2 (12.3). The frequencies of the homogygous common (A/A), heterozygous (A/C), and homozygous polymorphic (C/C) genotypes were 75%, 23% and 2% for DDs and 73%, 25%, and 2% for DAs, respectively. DDs and DAs were evaluated separately. Regression analyses controlled for age, premorbid intelligence, alcohol consumption, and education. Statistically significant associations with HgU (p<0.05) were found for nine measures among DDs (BEES Digit SpanForward and Backward, WMS-R Visual ReproductionN Correct, BEES Symbol DigitRate, BEES Finger TappingDom/Non-dom, and Alternate Partialed, Hand SteadinessFactor1, and BEES Tracking), and eight measures among DAs (BEES Digit SpanForward, BEES Symbol DigitRate, BEES Pattern Discrimination Rate, BEES Trailmaking B, BEES Finger TappingDom/Non-dom, and Alternate Partialed, Hand SteadinessFactor1, and Vibration SensitivityHits). CPOX4 status was associated with four measures in DDs (BEES Spatial SpanForward, BEES Pattern MemoryN Correct, BEES Symbol DigitRate, and BEES VigilanceHit) and five measures in DAs (BEES Digit SpanForward, WMS-R Visual ReproductionsN Correct, BEES Symbol DigitRate, BEES Simple and Choice Reaction TimeMove. Both groups experienced an additive effect (no interaction term) for HgU and the CPOX4 polymorphisms on the DigitRate whereas DAs also had additive effects for BEES Digit SpanForward and for Beck's Depression factor 'Worthlessness'. These exploratory findings suggest that the CPOX4 polymorphism may affect susceptibility for specific neurobehavioral functions associated with mercury exposure in human subjects.

Systemic administration of a calpain inhibitor reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat.

Increases in intracellular calcium and subsequent activation of calcium-activated proteases (e.g., calpains) may play a critical role in central nervous system injury. Several studies have implicated calpain activation following subarachnoid hemorrhage (SAH). This study evaluated the effect of a calpain inhibitor administration following SAH in the rat on behavioral deficits (postinjury days 1-5, employing a battery of well-characterized assessment tasks), and blood-brain barrier permeability changes (48 h post-SAH, quantifying the microvascular alterations according to the extravasation of protein-bound Evans Blue using a spectrophotofluorimetric technique). Rats were injected with 400 microl of autologous blood into the cisterna magna to induce SAH. Within 5 min after the surgical procedure, Calpain Inhibitor II or vehicle was continuously administered intravenously for 2 days. Results indicated that Calpain Inhibitor II treatment after SAH significantly improved (a) beam balance time (day 1, p < 0.05), but not beam balance score, (b) latency to traverse the beam on days 1-4 (day 1-3, p < 0.001; day 4, p < 0.01), and (c) loss in body weight on days 4-5 (p < 0.05). Evans Blue dye extravasation was significantly less in SAH Calpain Inhibitor II-treated rats compared to SAH vehicle-treated rats in seven out of the eight brain regions studied (p < 0.001, 0.01, and 0.05). These results suggest that pharmacological inhibition of a relatively selective, membrane-permeant calpain inhibitor can significantly reduce some pathophysiological SAH consequences, and indicate that the inhibition of calpain may be a beneficial therapeutic approach to reduce post-SAH global brain dysfunction.

Nitric oxide plays a key role in myelination in the developing brain.

Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates, but there is little information available about its effect on the developing brain. We explored the effects of both iNO and endogenous NO on developing white matter in rodents. Rat or mouse pups and their mothers were placed in a chamber containing 5 to 20 ppm of NO for 7 days after birth. Neonatal exposure to iNO was associated with a transient increase in central nervous system myelination in rats and C57BL/6 mice without any deleterious effects at low doses (5 ppm) or behavioral consequences in adulthood. Exposure to iNO was associated with a proliferative effect on immature oligodendrocytes and a subsequent promaturational effect. The role of endogenous NO in myelination was investigated in animals treated with the nitric oxides synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) in the neonatal period; this led to protracted myelination defects and subsequent behavioral deficits in adulthood. These effects were reversed by rescuing L-NAME-treated animals with iNO. Thus, we demonstrate considerable effect of both exogenous and endogenous NO on myelination in rodents. These data point to potential new avenues for neuroprotection in human perinatal brain damage.

Butyrylcholinesterase: impact on symptoms and progression of cognitive impairment.

The most successful approach for treating people with Alzheimer's disease to date has been by improving cholinergic transmission using cholinesterase inhibitors. Many of these drugs selectively inhibit acetylcholinesterase but some agents inhibit both acetylcholinesterase and butyrylcholinesterase. Recent evidence from studies examining butyrylcholinesterase in post mortem brain samples from dementia patients and examining the relationship between butyrylcholinesterase polymorphisms and the progression of cognitive impairment in dementia with Lewy bodies and Alzheimer's disease add to a body of work suggesting that butyrylcholinesterase is present in key brain areas and may influence the maturation of plaques in Alzheimer's disease. These accumulating data suggest that butyrylcholinesterase contributes to disease progression in people with dementia, which may be particularly important in individuals with more severe dementia as butyrylcholinesterase activity increases with disease development. It is a priority for future clinical trials to determine whether agents which inhibit butyrylcholinesterase and acetylcholinesterase have a greater clinical efficacy.