Susumu Kotani

Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction

Age-dependent increase of peroxidation of membrane fatty acids such as arachidonic acid (ARA) and docosahexaenoic acid (DHA) in neurons was reported to cause a decline of the hippocampal long-term potentiation (LTP) and cognitive dysfunction in rodents. Although supplementation of ARA and DHA can improve LTP and cognitive function in rodents, their effects in humans are unknown. The present work was undertaken to study whether ARA and DHA have beneficial effects in human amnesic patients. The subjects were 21 mild cognitive dysfunction (12 MCI-A with supplementation and 9 MIC-P with placebo), 10 organic brain lesions (organic), and 8 Alzheimers disease (AD). The cognitive functions were evaluated using Japanese version of repeatable battery for assessment of neuropsychological status (RBANS) at two time points: before and 90 days after the supplementation of 240 mg/day ARA and DHA, or 240 mg/day of olive oil, respectively. MCI-A group showed a significant improvement of the immediate memory and attention score. In addition, organic group showed a significant improvement of immediate and delayed memories. However, there were no significant improvements of each score in AD and MCI-P groups. It is suggested from these data that ARA and DHA supplementation can improve the cognitive dysfunction due to organic brain damages or aging.

Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys.

The G-protein coupled receptor 40 (GRP40) is a transmembrane receptor for free fatty acids, and is known for its relation to insulin secretion in the pancreas. Recent studies demonstrated that spatial memory and hippocampal long-term potentiation of rodents and cognitive function of humans are improved by a dietary supplementation with arachidonic and/or docosahexaenoic acids, which are possible ligands for GPR40. While free fatty acid effects on the brain might be related to GPR40 activation, the role of GPR40 in the central nervous system (CNS) is at present not known. Here, we studied expression and distribution of GPR40 in CNS of adult monkeys by immunoblotting and immunohistochemistry. Immunoblotting analysis showed a band of approximately 31 kDa consistent with the size of GPR40 protein. GPR40 immunoreactivity of was observed in the nuclei and/or perikarya of a wide variety of neurons including neurons in the cerebral cortex, hippocampus, amygdala, hypothalamus, cerebellum, spinal cord. In addition, astrocytes of the cerebral white matter, the molecular layer and multiform layer of the cerebral cortex, the subventricular zone along the anterior horn of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus showed GPR40 immunoreactivity. The present data first provide a morphological basis for clarifying the role of GPR40 in the primate CNS.

Synaptic plasticity preserved with arachidonic acid diet in aged rats

We examined whether synaptic plasticity was preserved in aged rats administered an arachidonic acid (AA) containing diet. Young male Fischer-344 rats (2 mo of age), and two groups of aged rats of the same strain (2 y of age) who consumed either a control diet or an AA ethyl ester-containing diet for at least 3 mo were used. In the Morris water maze task, aged rats on the AA diet had tendency to show better performance than aged rats on the control diet. Long-term potentiation induced by tetanic stimulation was recorded from a 300 microm thick hippocampal slice with a 36 multi-electrode-array positioned at the dendrites of CA1 pyramidal neurons. The degree of potentiation after 1 h in aged rats on the AA diet was comparable as that of young controls. Phospholipid analysis revealed that AA and docosahexaenoic acid were the major fatty acids in the hippocampus in aged rats. There was a correlation between the behavioral measure and the changes in excitatory postsynaptic potential slope and between the physiologic measure and the total amount of AA in hippocampus.

Effects of lanthanides on voltage-dependent potassium currents in bullfrog sympathetic neurons

The effects of lanthanides (La(3+), Gd(3+), Lu(3+) and Sm(3+)) on voltage-dependent potassium currents were studied in dissociated bullfrog sympathetic neurons. A-type current (I(A)) and M-type current (I(M)) were blocked by lanthanides (0.1-30 microM) with I(M) being much less sensitive to these ions than I(A). The order of potency was Gd(3+)>/=Lu(3+) approximately La(3+) approximately Sm(3+) for I(A) and Gd(3+)&z.Gt;Lu(3+) approximately La(3+)>Sm(3+) for I(M). The I(M) block occurred independently of its activation kinetics while the I(A) block was associated with a positive shift of the activation and inactivation curves. Gd(3+) (100 microM) blocked the delayed rectifier-type current (I(K)) by less than 20%; Lu(3+), La(3+) and Sm(3+) (100 microM for each) were without effect on I(K). It is concluded that I(A) was the most sensitive to lanthanides, and Gd(3+) was the most potent for all the currents in amphibian autonomic neurons.

Mechanisms underlying the M-current block by barium in bullfrog sympathetic neurons

Whole-cell/voltage-clamp recordings were made from dissociated bullfrog sympathetic neurons to examine the channel blocking actions of barium (3-2000 microM) on an M-type potassium current (I(M)). Barium (IC(50) approximately 105 microM) blocked I(M) without affecting the 50%-activation voltage ( approximately -35 mV) and the slope factor ( approximately 11 mV) of the activation curve. The results indicate that the barium block is independent of the kinetics of I(M).

Hyperpolarizing shift by quinine in the steady-state inactivation curve of delayed rectifier-type potassium current in bullfrog sympathetic neurons

Whole-cell recordings were made from dissociated bullfrog sympathetic neurons to examine the actions of quinine (1-100 microM) on the steady-state activation and inactivation curves of a delayed rectifier-type potassium current (I(K)). Quinine (EC50 approximately 8 microM) caused a hyperpolarizing shift (approximately 31 mV with 30 microM) in the inactivation curve of I(K) without significantly affecting its activation curve. Quinine (20 microM) was without effects on the voltage-dependence of a rapidly-inactivating A-type potassium current (I(A)). It is concluded that quinine can selectively modulate the voltage-dependence of I(K) in amphibian autonomic neurons.