Koho Miyoshi

Effects of cholinergic drugs on learning impairment in ventral globus pallidus-lesioned rats

The excitotoxin kainic acid (10 nmol/microliter) was used to produce bilateral lesions in the nucleus basalis magnocellularis (NBM) of rats which provides extensive cholinergic innervation to the cerebral cortex. The behavioral effects of physostigmine, THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrate hydrochloride) were investigated by observing locomotor activity, shock sensitivity and passive avoidance response in the NBM-lesioned rats. Evaluation of locomotor activity and shock sensitivity in the experimental animals did not reveal any sensorimotor disturbances caused by the lesions. Oral administration of 1 and 2 mg/kg physostigmine reduced the locomotor activity in the NBM-lesioned rats, while physostigmine (0.5 mg/kg), THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) had no effect on locomotor activity. Compared with the sham-operated controls, the NBM-lesioned rats exhibited a significantly lesser deficit in the retention of the passive avoidance response. THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) elicited good retention of the passive avoidance response. Rats with NBM lesions showed impaired acquisition of a passive avoidance response when trained repeatedly at 24-h intervals. Also, when post-training NBM lesions were induced, there was rapid extinction of the acquired passive avoidance response. THA or NIK-247 administered at doses of 3 mg/kg significantly increased response latencies of post-trained NBM-lesioned rats. THA or NIK-247 administered once a day in doses of 1 or 3 mg/kg p.o. produced a very significant increase of acetylcholine in the cerebral cortex of NBM-lesioned rats after the 21st administration. These finding suggest that THA and NIK-247 exert an ameliorating effect on memory disturbance induced by NBM lesions in rats.

An ultrastructural study of Pick bodies.

SummaryWe report the results of an ultrastructural study of Pick bodies (PB). A histogram constructed with the maximal width of each filamentous component in PB revealed a wide range of sizes among the filaments, in contrast to the unique composition of the paired helical filaments (PHF) seen in the neurofibrillary tangle of Alzheimer type (NFT-AT). Morphologically, three groups of filaments could be distinguished. The first group consisted of straight smooth-surfaced filaments of 10–14 nm diameter, which were presumably altered neurofilaments. The second one was of straight smooth-surfaced “tubules” of 15–22 nm diameter, smaller than normal microtubules. The third one was of PHF thought to be formed by a pair of filaments of the first group. The PHF found in PB differed from PHF of NFT-AT in the distance between corssovers, and rather resembled the loosely interwinding PHF reported in NFT of progressive supranuclear palsy.

Impairment in the acquisition of passive and active avoidance learning tasks due to bilateral entorhinal cortex lesions

The relationship between the entorhinal cortex and learning behavior was examined. The initial stage of Alzheimers disease has been shown to be characterized by neuropathological alteration in the entorhinal cortex, with the appearance of the greatest number of neuronal tangles and severe neuronal loss in comparison with other brain regions involved. This entorhinal cortex, because of its anatomical relationship to the hippocampus, may play a crucial role in memory formation. In this study, rats with bilateral ibotenic acid-induced lesions of the entorhinal cortices were tested for acquisition of passive and active avoidance learning tasks. These animals displayed no sensorimotor disturbances as shown by evaluation of locomotor activity and shock sensitivity. However, they did show impair acquisition of passive and active avoidance responses. On the other hand, when the lesions were induced after training, there was no extinction of the acquired passive and active avoidance responses. The results demonstrate the importance of the entorhinal cortex in learning acquisition and indicate that rats with partial neuronal loss in the entorhinal cortex may be a useful model for studying the memory disturbance of Alzheimers disease.

Unusual paired helical filaments in progressive supranuclear palsy

SummaryUnusual paired helical filaments (PHF) coexisting with single filaments were observed in neurofibrillary degeneration (NFD) in the globus pallidus, subthalamic nucleus, substantia nigra, and pontine tegmentum of a typical case of progressive supranuclear palsy (PSP). Each filament had a diameter of 10–12 nm and showed central low density and a smooth contour. The thickest portion of a pair was 22–24 nm in diameter. The periodicity of twist varied from 150 nm to 300 nm, but each PHF had regular periodicity. The present ultrastructural, finding is unusual in the neurofibrillary pathology of PSP, and is also different from the PHF found in Alzheimer type NFD.

An autopsy case of mitochondrial encephalomyopathy with prominent degeneration in olivo-ponto-cerebellar system

SummaryWe describe a sporadic case of adult-onset, complex I deficiency mitochondrial encephalomyopathy (MEM), the clinical and pathological features of which failed to fit any of the known subgroups of MEM, such as Kearns-Sayre syndrome, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes or myoclonus epilepsy with ragged-red fibers. Clinically, this patient had only progressive cerebellar ataxia, generalized muscle weakness and hearing loss. The principal finding at autopsy was degeneration of the olivoponto-cerebellar system. This case suggests that mitochondrial disease could underlie some cases of olivoponto-cerebellar atrophy.

Reversal of learning impairment in ventral globus pallidus-lesioned rats by combination of continuous intracerebroventricualr choline infusion and oral cholinergic drug administration

The effects of separate or combined oral administration of THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b] quinoline monohydrate hydrochloride) and intracerebroventricular choline infusion using an osmotic minipump were investigated by observing locomotor activity, shock sensitivity, passive avoidance response and cerebral choline and acetylcholine contents in the bilateral ventral globus pallidus-lesioned rat. Evaluation of locomotor activity and shock sensitivity revealed no sensorimotor disturbances caused by combined administration. Intracerebroventricular choline infusion (100 mumol/day) and oral THA or NIK-247 administration (0.5 mg/kg) had no effect on the acquisition of the passive avoidance response, while the combination of oral THA or NIK-247 administration (0.5 mg/kg) and intracerebroventricular choline infusion (100 mumol/day) elicited good acquisition of passive avoidance learning and produced a significant increase of choline and acetylcholine in the cerebral cortex of the bilateral ventral globus pallidus-lesioned rat. These findings suggest that continuous intracerebroventricular choline infusion may intensify the ameliorating effect of THA or NIK-247 on learning disturbance.

Cerebellar degeneration induced by acetyl-ethyl-tetramethyl-tetralin(AETT).

SummaryThe neurotoxicity of acetyl-ethyl-tetramethyltetralin (AETT) was investigated following its percutaneous administration to rats. Animals exposed to a high-dose of AETT developed a gait abnormality that progressed to severe ataxia. Microscopic examinations revealed remarkable cerebellar changes in addition to a widespread accumulation of ceroid-like pigmentation in the neuronal cytoplasm. The cerebellar changes, especially in the vermis and intermediate part, were characterized by selective degeneration and depopulation of Purkinje cells, and a spongy state of the cerebellar white matter, which was formed in splits in the intraperiod lines within the myelin sheath. In contrast, there were only negligible changes of granule cells and other neuronal elements. Accumulation of ceroid-like pigments and selective damage to the Purkinje cells seen in the present study together provide a basis for understanding the pathogenesis of AETT intoxication and distinguish it from other experimentally induced conditions. Thus, high-dosage AETT intoxicated rats may constitute a new experimental model of cerebellar degeneration.

Effects of AETT-induced neuronal ceroid lipofuscinosis on learning ability in rats.

Abstract: The behavioral effects of ceroid‐lipofuscin accumulation, induced by intraperitoneal administration of acetyl‐ethyl‐tetramethyl‐tetralin (AETT) in Wistar rats for 3 months, were examined in the present studies. A significant increase in neuronal ceroid‐lipofuscin was demonstrated neuropathologically as well as morphometrically. Although the AETT‐intoxicated rats showed neither alteration of locomotor activity nor shock sensitivity, a significant impairment of learning ability, especially an acquisition trial in passive avoidance tests, was observed. Results of the present studies indicate the possibility that a diffuse lipofuscin accumulation causes a learning impairment in rats. The results also imply the possibility of a significant role of age‐related lipofuscin accumulation in the dementing processes of human especially in the elderly.

Effect of Benzodiazepine Derivatives on Amygdaloid-Kindled Convulsion

An evaluation of the anticonvulsant effect of five kinds of benzodiazepine derivatives using amygdaloid‐kindled rats yielded the following pharmacological properties of benzodiazepine derivatives: (1) Bromazepam, lorazepam and nitrazepam block the behavioral seizure response and also shorten the after‐discharge duration simultaneously in both primary and secondary epileptogenic foci. (2) Diazepam has little effect on shortening the after‐discharge duration at least in the primary epileptogenic focus though it blocks the behavioral seizure response. (3) Although clonazepam can block the behavioral seizure response and shorten the after‐discharge duration, further investigations are necessary to define its efficacy.

Ultrastructural observations on the vincristine-induced neuronal crystalloid inclusion in young rats

SummaryVincristine-induced crystalloid inclusions were examined in the neurons and neuronal processes of young rats by the electron microscope (EM) equipped with a tilting stage. Using a computer system that reproduces three-dimensional organization, an optical transformation method was applied to the microtubules and neurofilaments in an attempt to clarify the morphological appearance and internal pattern of crystalloid inclusions. The dimensional models obtained were compared with actual EM photographs, and the characteristic ultrastructural component and morphology were drawn out.Basically, a crystalloid inclusion is composed of four strands of intermediate 10 nm neurofilaments connected to one another by four side-arms producing a circular profile on a transverse section. These four side-arms seemed to arise from nodules within the filaments at regular intervals simulating a bead-like appearance. These data did not significantly differ from those obtained from EM images. Characteristically, these crystalloid inclusions began to appear 6 h after the administration of 10−3 M vincristine sulfate and persisted up to a period of 6 days. Beyond that, however, these inclusions were no longer demonstrable suggesting a transient state. This was in contrast to neurofibrillary tangles which appeared to be permanent changes.