D. Ekuni, T. Tomofuji, K. Irie, T. Azuma, Y. Endo, K. 2Kasuyama…2011
, Occlusal Disharmony Increases Amyloid-β in the Rat Hippocampus
Abstract
Amyloid-β plays a causative role in Alzheimer’s disease. Occlusal disharmony causes chronic psychological stress, and psychological stress increases amyloid-β accumulation. The purpose of the present study was to investigate whether occlusal disharmony-induced psychological stress affects the accumulation of amyloid-β and its related gene expressions in the rat hippocampus. Eight-week-old male Wistar rats (n = 18) were divided into three groups of six rats each: (1) a control group that received no treatment for 8 weeks; (2) an occlusal disharmony group that underwent cutoff maxillary molar cusps for 8 weeks; and (3) a recovered group that underwent cutoff maxillary molar cusps for 4 weeks followed by recovery for 4 weeks. Occlusal disharmony increased plasma corticosterone levels in a time-dependent manner. Levels of amyloid-β 40 and 42, glucocorticoid receptor (Gr) protein, and cleaved caspase 3 (Casp3) as well as gene expressions of amyloid precursor protein, beta-secretase, Casp3, and Gr in the hippocampus in the occlusal disharmony group were significantly higher than those in the control group (P < 0.016). These findings were significantly improved by recovery of occlusion (P < 0.016). These results indicate that psychological stress induced by occlusal disharmony reversibly induces amyloid-β 40 and 42 in the rat hippocampus through the glucocorticoid signal.

TRADUCTION :
Les Amyloid-β jouent un rôle causatif dans la maladie d’ALZHEIMER. Le déséquilibre de l’occlusion induit un stress psychologique chronique et le stress psychologique augmente l’accumulation des amyloids-β. Le but de cette présente étude était de rechercher si la déséquilibre de l’occlusion induite par un stress psychologique affectait l’accumulation. d’amyloid-ß dans hippocampe du rat Ces résultats indiquent que le stress psychologique induit par la déséquilibre de l’occlusion de façon réversible induit des amyloid-β 40 et 42 dans l’hippocampe du rat par le biais d ‘un signal dû aux glucocorticoïdes.

Commentaire : Pr Francis HARTMANN

On applique chez des rats au niveau d’une hémi arcade dentaire une épaisseur de résine auto-collante.
On a créé ainsi un déséquilibre d’épaisseur.
Cette épaisseur, placée sur quelques dents : prémolaires molaires par exemple, induit, en comparaison avec des rats témoins une libération explosive d’hormones du stress . ces hormones d’origine hypothalamiques sont :
la corticostérone plasmatique (glucocorticoïdes) la nor-adrénaline.
A ce stade un stress psychologique a donc été scientifiquement créé chez un lot de rats observable par le biais de la comparaison des taux observés dans chaque lot respectif. On enlève cette épaisseur placée entre les dents. Malgré ce : savez vous combien de temps persiste ce taux élévé d’hormones du stess ?
Réponse : 3 mois !
Ce n’est pas fini, les observations scientifiques rigoureuses mettent én évidence que ce stress psychologique, dû à un signal provoqué par les glucocorticoïdes, induit la formation de plaques amyloîdes-β 40 et 42 dans l’hippocampe des rats.

M.P. Aresol, M.T. Giralt’, B. Sainz2, M. Prieto’, P. Garcia-Vallejo2, and F.M. Gomez 2*

Occlusal disharmonies have classically been thought to be involved in the etiopathogenesis of bruxism, as have, more recently, alterations in central neurotransmission, particularly dopaminergic neurotransmission. However, the connection between these two factors has still not been established. In this study, we assessed the effects of diverse occlusal disharmonies, maintained for either 1 day or 14 days, on neurochemical indices of dopaminergic and noradrenergic activity in the striatum, frontal cortex, and hypothalamus of the rat. The in vivo activity of tyrosine hydroxylase, determined as the accumulation of 3,4-dihydroxyphenylalanine (DOPA), 30 min after the administration of 3-hydroxybenzylhydrazine, a DOPA decarboxylase inhibitor, and dopamine and noradrenaline contents were quantified by high-performance liquid chromatography with electrochemical detection. The wearing of an acrylic cap on both lower incisors for 1 day induced a significant increase in DOPA accumulation in the regions analyzed, with parallel increases in dopamine levels in the hypothalamus and dopamine and noradrenaline in the frontal cortex. After the cap was maintained for 14 days, DOPA accumulation tended to return to control values, except in the left striatum, thereby causing an imbalance between hemispheres. In contrast, 1 or 14 days after the lower left and the upper right incisors were cut, less pronounced changes in catecholaminergic neurotransmission were found in the brain areas studied. Moreover, the cutting of one lower incisor did not modify either DOPA accumulation or dopamine and noradrenaline contents in the striatum or hypothalamus. These results provide experimental evidence of a modulation of central catecholaminergic neurotransmission by occlusal disharmonies, being dependent on the nature of the incisal alteration and on the time during which it was maintained. (…).

The present study provides evidence of a modulation of central catecholaminergic activity provoked by occlusal disharmonies.
This modulation was dependent on the type of incisaI alteration assessed and on the time during which it was maintained. Thus, an enhancement in the in vivo activity of TH was found in the three brain regions analyzed (striatum, frontal cortex, and hypothalamus), one day after the placement of an incisal cap, which could reflect a general activation of central catecholaminergic neurotransmission, as a consequence of the presumed submaximal oral sens ory stimulation provoked by the cap (Pohto et al., 1979). However, one day after the contralateral cutting of the lower left and upper right incisors, or the unilateral cutting of the lower left incisor, no changes were found in this neurochemical index. Electrophysiological and biochemical studies have provided evidence of changes in nigrostriatal dopaminergic activity in response to different types of somatosensory stimulation (Maeda and Mogenson, 1982; Keller et al., 1983 Abercrombie et al., 1989; Pei et al., 1990; Castro et al., 1996).
More specifically, changes in orofacial sensory inputs affecting neural activity in various basal ganglia structures have been reported (Harper et al., 1979; Schneider and Lidsky, 1981). In addition, a transitory increase in the release and subsequent metabolism of DA has been described after unilateral acute tactile vibrissae stimulation (Adams et al., 1991). Furthermore, in accordance with the enhanced striatal TH activity found after the wearing of the incisaI cap, other studies have also observed increases in the striatal biosynthetic dopaminergic activity after alterations in orofacial sensory inputs or peripheral stimulation (Schwarting et al., 1994; Castro et al., 1996).
Although the in vivo activity of TH in the striatum is proportional to the impulse traffic of nigrostriatai dopaminergic neurons (Murrin and Roth, 1976), no changes in striatal DA contents were found, in either brain hemisphere, after the incisaI cap was maintained for 1 day. Nevertheless, the possibility that the placement of the cap induces an immediate enhancement in the release of this neurotransmitter cannot be disregarded. However, since in this study it was necessary to anesthetize the animaIs lightly to alter occlusion, it was not possible to measure striatal DA content directly after the placement of the cap. Therefore, the increase referred to in striatal TH activity could be due to a regulatory mechanism in biosynthetic activity, to compensate for the possible enhanced utilization of this neurotransmitter caused by the sustained oral stimulation elicited by the acute presence of an occlusal disharmony which raises occlusion. The response of central catecholaminergic activity to somatosensory stimuli also occurs in other dopaminergic structures. Thus, increases in this activity in the frontal cortex have been reported after exp os ure to somatosensory stimuli, with mesocortical dopaminergic neurons apparently being more prone to modulation under aversive conditions than those of the nigrostriatal system (Abercrombie et al., 1989; Cenci et al., 1992). In agreement with this, we found that the increase in TH activity in the frontal cortex was even more pronounced than that found in the striatum, when the incisaI cap was maintained on both lower incisors for 1 day. In this context, enhanced biosynthetic dopaminergic activity has been observed more frequently in the mesocortical than in the nigrostriatal neurons (Reinhard et al., 1982; Kramarcy et al., 1984; Iuvone and Dunn, 1986). However, this increase cannot be attributed to an exclusive activation of either dopaminergic or noradrenergic neurons, sin ce this cortical area receives both innervations. Furthermore, there was not only a notable simultaneous increase in frontocortical TH activity and in DA content, elicited by the alteration of occlusion for 1 day, but also an enhancement of NA content, although much less relevant.
The enhancement of frontocortical TH activity and DA content found in our study may be explained by the biochemical and pharmacological characteristics of mesocortical neurons, which differ from other midbrain dopaminergic neurons in that their regulatory capacity for synthesis inhibition is relatively deficient (for review, see Roth and E1sworth,1995). The modulation of central catecholaminergic activity found in the hypothalamus, when an incisal cap was maintained for 1 day, was similar to that found in the frontal cortex. Both frontocortical and hypothalamic noradrenergic projections are particu1arly sensitive to somatosensory stimuli (Cenci et al., 1992; Shibasaki et al., 1995), and the increase in hypothalamic TH activity found in this study is in accordance with the enhancement of the biosynthetic activity reported by others, in different noradrenergic brain areas, after exposure to diverse somatosensory stimuli (Reinhard et al., 1982; Kramarcy et al., 1984; Smith et al., 1991). There is experimental evidence to suggest that the hypothalamus is involved in bruxism (Landgren and Disson, 1980), and its electrical stimulation induces masticatory muscle hyperactivity (Weiner et al., 1993).
In this context, in rodents, a clear gnawing response has been observed after intrahypothalamic NA administration (Swiergiel and Peters, 1987), and changes in neuronal activity have been registered in this brain area, after stimulation of the periodontal region or tooth pulp (Hamba et al., 1990; Trub and Mei, 1991). Therefore, the presence of an acrylic cap, which must provoke strong oral stimulation, particularly in the periodontal mechanoreceptors, may induce changes in catecholaminergic neurotransmission in the hypothalamus and thus contribute to the masticatory muscle hyperactivity. Due to the fact that occlusal alterations may he present for long periods of time in humans, we aiso assessed the possible changes in central catecholaminergic neurotransmission after the prolonged presence of the occlusal disharmonies used in this study. Globally, the results obtained showed that the enhanced catecholaminergic activity found in the frontal cortex and hypothalamus, 24 hrs after the placement of the incisaI cap, tended to return to control values when this occlusal disharmony was maintained for 14 days. The fact that the increased TH activity is effectively restored to control values is in accordance with the normalization of the biosynthetic catecholaminergic activity observed in sorne studies after repeated exposure to the same somatosensory stimulus in certain noradrenergic brain structures (Smith et al., 1991), and in terminal fields of the mesocortical dopaminergic system (Kramarcy et al., 1984).
However, in this study, an imbalance between both brain hemispheres in the activity of striatal TH activity, which is regulated by D-2 autoreceptors, was found after the incisaI cap was maintained for 14 days. It has been suggested that, for an adequate control of movement to be ensured, there must be a balance between the dopaminergic activities of both brain hemispheres. In fact, in the rat, an interhemispheric regulatory mechanism exists in normal conditions whose role is to compensate for the intrinsic asymmetries in the central dopaminergic system (Rodriguez et al., 1990). Nevertheless, under certain conditions, this regulatory mechanism could break down, and it has been reported that there is an asymmetrical utilization of DA in the frontal cortices of both brain hemispheres, as a response to uncontrollable somatosensory stimuli (Carlson et al., 1993).
On the other hand, prolonged changes in orofacial sensory inputs affected the organization of crossed and uncrossed nigrostriatal projections in a time-dependent manner (Steiner et al., 1992), supporting the existence of a certain degree of plasticity in the central dopaminergic system (Huston et al., 1990). In addition, changes in striatal D-2-like receptors seem to play a relevant role in the etiopathogenesis of certain neurological disturbances involving frequent abnormal jaw movements or oral stereotyped responses, such as dyskinesia, dystonia, or schizophrenia, diseases in which a central dopaminergic alteration is suspected as the underlying cause (Casey, 1995; Perlmutter et al., 1997; Schrôder et al., 1997). Moreover, a side imbalance in striatal D-2 receptors has been associated with the appearance of lateralized dystonic movements as well as with sleep bruxism (Hierholzer et al., 1994; Lobbezoo et al., 1996, 1997). Prolonged alterations in orofacial sensitivity, e.g., problems related to teeth or to the use of dental prostheses in humans, seem to precede the occurrence of abnormal orofacial or jaw movements in either dystonia or dyskinesia (Ghika et al., 1993; Myers et al., 1993). Although there is no direct evidence, the interhemispheric imbalance in DA synthesis described in the present study might be a consequence of changes in D-2 autoreceptors in response to the sustained, prolonged modification in the oral sensitivity caused by certain occlusal disharmonies, and thus contribute to the appearance of oral parafunctional movements, particularly in those conditions which imply a central dopaminergic preponderance (Nishioka and Montgomery, 1988).
Further studies assessing the effects of prolonged occlusal alterations on striatal D-2 receptor functionality and its possible repercussion on oral behavior will be necessary to elucidate this hypothesis. The lack of changes in central dopaminergic activity 1 day after the contralateral or unilateral cutting of the incisors was in clear contrast to the modulation found after the raising of occlusion by the placement of the cap. In agreement with these results, there was also an absence of change in striatal DA content 4 hrs after the unilateral removal of the vibrissae in rats (Schwarting et al., 1990). In a previous study, we found that the placement of an incisaI cap, but not the unilateral cutting of the lower left incisor, enhanced the ability of apomorphine to induce nonfunctional masticatory activity (G6mez et al., 1998). The incisaI alteration, which prevents occlusal contact with the remaining incisors, must logically lead to a reduction of the proprioceptive inputs from the periodontal mechanoreceptors.
A lack of oral sensory inputs from the oral cavity might lead to a concomitant decrease of the sensory information being transmitted to the nigrostriatal dopaminergic system. This could explain the slight reduction in the in vivo striatal TH activity and the increase in DA content found after the incisors were maintained out of occlusion for 14 days. Nevertheless, hypothalamic and frontocortical TH activity remained unmodified when the occlusal disharmony provoked by the contralateral cutting of the incisors was maintained for the same period. Due to the primordial role of the teeth in rodents, the possible stress generated by certain occlusal disharmonies (Budtz-Jergensen, 1981) could also contribute to the neurochemical modulation described in this study. Hence, it is widely accepted that during stressful events, adaptive changes in central catecholaminergic activity do occur and are essential for the organism to deal effectively with the ongoing stress (Anisman and Zacharko, 1990).
In this context, it has been described that diverse stressors have the ability to activate the dopaminergic system asymmetrically, this imbalance being more pronounced when the stressful condition is prolonged or uncontrolled by the organism (Carlson et al., 1991, 1993). Among other responses, stress induces the release of glucocorticoids, with a consequent severe hypertrophy of the adrenal glands and also a loss of body weight (McEwen et al., 1988).
However, we must point out that while a significant reduction in the gain of body weight was observed when the incisaI cap was maintained for 14 days, no adrenal gland hypertrophy was found in any of the experimental groups subjected to prolonged occlusal disharmonies. In summary, although the results obtained from animaIs cannot be directIy applied to humans, the results presented provide evidence of a modulation of central catecholaminergic activity, which was dependent on the type of occlusal disharmony generated and on the time during which it was maintained.
Our data are also consistent with previous findings that have indicated the relevant role of central dopaminergic and noradrenergic systems in modulating a wide spectrum of oral behavior, as well as in mediating the organism’s response to somatosensory stimuli.
Finally, our results point toward the possible involvement of occlusal disharmonies, especially those that raise occlusion, in the putative role of central catecholaminergic neurotransmission in the etiopathogenesis of certain parafunctional masticatory movements. (…)

Key words: occlusal disharmonies, DOPA accumulation, central catecholaminergic neurotransmission, bruxism.

T. Yoshihara*, Y. Matsumoto, and T. Ogura
Department of Pediatric Dentistry, Kagoshima University
School of Dentistry, Sakuragaoka 8-35-1, Kagoshima 890-0075, Japan; *corresponding author,
tyoshi(denta.hal.kagoshima-u.ac.jp
J Dent Res 80(12):2089-2092, 2001

ABSTRACT
Few neuro-endocrinological studies have examined the relationship between occlusal disharmony and
stress. To determine the effect of occlusal disharmony on the central nervous system, we measured plasma corticosterone and extracellular noradrenaline in the vicinity of the hypothalamic paraventricular nucleus in rats both with and without incisal caps. After the caps were set, plasma corticosterone and extracellular noradrenaline levels gradually increased, reaching a peak at 8.5 and 6.5 hours, respectively, after which they decreased. Furthermore, plasma corticosterone and extracellular noradrenaline levels increased in a circadian fashion around the onset of the dark phase in rats without caps, but not in rats with caps. These results suggest that occlusal disharmony causes chronic stress in the rat.

à venir

Kentaro Yamada, Yumie Ono, Kin-Ya Kubo, Yokosuka Kanagawa, Japan

Occlusal disharmony sometimes causes not only stiffness of neck but also psychiatrie depression, suggesting that the condition of oral cavity may affect the central nervous system. Dynorphin A is an endogenous opioid peptide that specifically binds the K-opioid receptor and has a protective raie against stress. Dynorphinergic nervous system is intensely distributed in the amygdala and hippocampus that are coping areas with stress. As a model of malocclusion, we placed dental resin on the molars to increase the occlusal vertical dimension (bite-raise). After various survival times, we analyzed the amygdala and hippocampus by immunohistochemistry and immunosorbent assay (ELISA). Furthermore, the effects on learning and memory were assessed by Morris water maze test. In the amygdala, the levels of dynorphin A were increased on the 1 st day after increasing the vertical dimension as indicated by immunohistochemical and ELISA assessments. The levels of dynorphin A returned to control levels on the 5th day. In the hippocampus, there were no noticeable changes in dynorphin A levels. The water maze test indicated that increasing the vertical dimension caused longer escape latency times on the 3rd day compared to those of sham-operated group. However, the bite-ra ised mice trea ted wi th a dynorphin antagonist, nor-binaltorphimine, showed similar escape latency times to the times of sham-operated group, even on the 3rd day. These results suggest that ocdusal disharmony causes stress resulting in a transient increase of dynorphin A levels at least in the amygdala and that the increased dynorphin A levels transiently impair learning and memory.

Keywords: amygdala: dunorphin: hippocampus: malocclusion: stress

Tobok1.1 J. Exp. Med., 2013 May. 230 ( 1). 49-57. 0 2013 Tohobl Ulùversity Medical Press