Adjuvant Arthritis Disrupts Normal Chronobiological Organization

We have examined a number of immune and neuroendocrine circadian rhythms in FCA-injected rats by looking for changes in the preclinical phase of arthritis (2 to 3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection) (Tables 3.1 to 3.3). Generally, changes in circadian rhythms in lymph node immune function tended to be more profound at the preclinical phase of the disease. For example, B-cell- and T-cell-mediated mitogenic activity of lipopolysaccharide (LPS) and concanavalin (Con A), respectively, were modified in amplitude or acrophase during the preclinical phase (Esquifino, Castrillon, Chacon, Cutrera, and Cardinali 2001) while exhibiting few or none changes during the acute phase of experimental arthritis (Garcia Bonacho, Cardinali, Castrillon, Cutrera, and Esquifino 2001) (Table 3.1). Similarly, 24-h variations of B and T cells, as well as of CD4+ (T helper) and CD8+ (T cytolytic) cells became significantly changed during the preclinical phase (Castrillon, Esquifino, Varas, Zapata, Cutrera, and Cardinali 2000; Esquifino et al. 2001), with absence of changes during the acute phase (Garcia Bonacho et al. 2001). In the case of lymph node cell proliferation and local autonomic nerve activity, the increase in amplitude and mesor of rhythms found in the preclinical phase of arthritis was higher than that observed as the disease progressed (Cardinali, Brusco, Selgas, and Esquifino 1998a). Therefore, the results suggest that some sort of homeostatic compensation of initial changes in circadian rhythmicity of immune changes occurs with the development of arthritis (Table 3.1). As far as changes in neuroendocrine rhythmicity during rat's arthritis, early data had indicated in FCA-injected rats that the 24-h organization of the biologic responses was altered. For example, morning-evening differences in circulating ACTH and corticosterone disappeared by days 7 to 21, and between days 6 and 8 after FCA injection a loss of the adrenocortical ODC circadian rhythm of activity was found (Neidhart 1996).

Table 3.1. Summary of changes in circadian rhythms of submaxillary lymph node immune responses during the preclinical (3rd day) and acute (18th day) phases of Freund's adjuvant arthritis in rats. (Results from Cardinali et al. 1996a, 1997a, 1998a, 1998b; Castrillon et al. 2000; Esquifino et al. 1996, 2001; Garcia Bonacho et al. 2001.)

Table 3.1. Summary of changes in circadian rhythms of submaxillary lymph node immune responses during the preclinical (3rd day) and acute (18th day) phases of Freund's adjuvant arthritis in rats. (Results from Cardinali et al. 1996a, 1997a, 1998a, 1998b; Castrillon et al. 2000; Esquifino et al. 1996, 2001; Garcia Bonacho et al. 2001.)

24-h rhythms

Amplitude

Acrophase

Mean

Preclinical phase

Cell proliferationa

Increased

Unchanged

Increased

Mitotic response to Con A

Decreased

Unchanged

Unchanged

Mitotic response to LPS

Unchanged

Changed

Unchanged

NK cells

Absence of rhythm

Absence of rhythm

Unchanged

B cells

Increased

Unchanged

Increased

T cells

Unchanged

Unchanged

Unchanged

B-T cells

Induction of rhythm

Induction of rhythm

Increased

CD4+ cells

Induction of rhythm

Induction of rhythm

Unchanged

CD8+ cells

Suppression of rhythm

Suppression of rhythm

Unchanged

CD4+-CD8+ cells

Induction of rhythm

Induction of rhythm

Unchanged

Noradrenergic activityb

Increased

Unchanged

Increased

Cholinergic activityc

Increased

Unchanged

Increased

Acute phase

Cell proliferationa

Increased

Unchanged

Increased

Mitotic response to Con A

Unchanged

Unchanged

Unchanged

Mitotic response to LPS

Unchanged

Unchanged

Unchanged

B cells

Unchanged

Unchanged

Unchanged

T cells

Unchanged

Unchanged

Unchanged

CD4+ cells

Unchanged

Unchanged

Unchanged

CD8+ cells

Unchanged

Unchanged

Unchanged

Noradrenergic activityb

Increased

Unchanged

Increased

Cholinergic activityc

Increased

Unchanged

Increased

5-HT

Absence of rhythm

Absence of rhythm

Unchanged

Inhibitory amino acidsd

Unchanged

Unchanged

Unchanged

Excitatory amino acidse

Unchanged

Unchanged

Unchanged

' Estimated from ornithine decarboxylase activity changes. b Estimated from tyrosine hydroxylase activity and neuronal NE uptake. c Estimated from 3H-acetylcholine synthesis and neuronal choline uptake. d Aspartate, glutamate. e GABA, taurine.

In our own studies conducted during the preclinical phase of arthritis, a significant effect of immune-mediated inflammatory response on diurnal rhythmicity of circulating ACTH, growth hormone (GH), prolactin and thyrotropin (TSH) release was found, and was partially sensitive to immunosuppression by cyclosporine (Selgas et al. 1998) (Table 3.2). Further experiments indicated that hypothalamic levels of corticotrophin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), GH-releasing hormone (GHRH), and somatostatin were altered in the preclinical phase of arthritis (Esquifino et al. 1999). In the median eminence, adjuvant's vehicle-injected rats exhibited significant 24-h variations for the four hypophysiotropic hormones examined, with maxima at noon.

Table 3.2. Summary of changes in circadian rhythms of hypothalamic and hypophysial hormones and neurotransmitters, pineal melatonin and plasma proteins during the preclinical (3rd day) phases of Freund's adjuvant arthritis in rats.

24-h rhythms_Amplitude_Acrophase_Mean

Preclinical phase Serum

24-h rhythms_Amplitude_Acrophase_Mean

Preclinical phase Serum

ACTH

Unchanged

Unchanged

Augmented

Prolactin

Unchanged

Unchanged

Augmented

GH

Absence of rhythm

Absence of rhythm

Decreased

TSH

Suppression of rhythm

Suppression of rhythm

Decreased

LH

Suppression of rhythm

Suppression of rhythm

Decreased

Albumin

Absence of rhythm

Absence of rhythm

Unchanged

a-1 globulin

Decreased

Unchanged

Unchanged

a-2 globulin

Decreased

Unchanged

Decreased

P-globulin

Absence of rhythm

Absence of rhythm

Unchanged

y-globulin

Absence of rhythm

Absence of rhythm

Unchanged

Median eminence

CRH

Decreased

Unchanged

Decreased

TRH

Suppression of rhythm

Suppression of rhythm

Decreased

GHRH

Decreased

Unchanged

Decreased

Somatostatin

Decreased

Unchanged

Decreased

NE

Decreased

Unchanged

Unchanged

DA turnover

Unchanged

Changed

Unchanged

5-HT turnover

Suppression of rhythm

Suppression of rhythm

Decreased

Anterior hypothalamus

CRH

Suppression of rhythm

Suppression of rhythm

Decreased

TRH

Suppression of rhythm

Suppression of rhythm

Decreased

GHRH

Unchanged

Changed

Unchanged

Somatostatin

Unchanged

Changed

Unchanged

NE

Decreased

Unchanged

Decreased

DA turnover

Decreased

Unchanged

Unchanged

5-HT turnover

Decreased

Unchanged

Decreased

Medial hypothalamus

CRH

Unchanged

Unchanged

Unchanged

TRH

Suppression of rhythm

Suppression of rhythm

Decreased

GHRH

Unchanged

Unchanged

Unchanged

Somatostatin

Unchanged

Unchanged

Unchanged

NE

Decreased

Unchanged

Decreased

DA turnover

Decreased

Unchanged

Decreased

5-HT turnover

Decreased

Unchanged

Unchanged

Posterior hypothalamus

CRH

Unchanged

Unchanged

Unchanged

TRH

Unchanged

Unchanged

Unchanged

GHRH

Unchanged

Unchanged

Unchanged

Somatostatin

Unchanged

Unchanged

Unchanged

NE

Unchanged

Changed

Unchanged

DA turnover

Decreased

Unchanged

Decreased

5-HT turnover

Unchanged

Changed

Unchanged

Pineal gland

Melatonin

Unchanged

Unchanged

Unchanged

These 24-h rhythms were inhibited or suppressed 3 days after FCA injection. The administration of the immunosuppressant drug cyclosporine impaired the depressing effect of FCA injection on CRH, TRH, and somatostatin content in median eminence, but not that on GHRH. The activity of cyclosporine was less evident in other hypothalamic regions examined (Esquifino et al. 1999). Generally, a decrease amplitude or mesor of transmitter rhythms were detectable, mainly in anterior and medial hypothalamic regions (Castrillon, Cardinali, Pazo, Cutrera, and Esquifino 2001) (Table 3.2). We also examined the changes in circadian rhythms of CNS and hypophysial hormones and neurotransmitters during the acute phase of Freund's adjuvant arthritis (i.e., 18 days after FCA administration) (Table 3.3).

Table 3.3. Summary of changes in circadian rhythms of hypothalamic and hypophysial hormones and neurotransmitters, pineal melatonin and plasma proteins during the acute (18th day) phase of Freund's adjuvant arthritis in rats.

24-h rhythms

Amplitude

Acrophase

Mean

Acute phase

Serum

ACTH

Suppression of rhythm

Suppression of rhythm

Augmented

FSH

Unchanged

Unchanged

Unchanged

LH

Suppression of rhythm

Suppression of rhythm

Decreased

Prolactin

Unchanged

Unchanged

Unchanged

Testosterone

Suppression of rhythm

Suppression of rhythm

Decreased

GH

Absence of rhythm

Absence of rhythm

Decreased

TSH

Suppression of rhythm

Suppression of rhythm

Unchanged

Anterior hypothalamus

NE

Suppression of rhythm

Suppression of rhythm

Unchanged

DA turnover

Suppression of rhythm

Suppression of rhythm

Unchanged

Medial hypothalamus

NE

Unchanged

Unchanged

Unchanged

DA turnover

Induction of rhythm

Induction of rhythm

Unchanged

Posterior hypothalamus

NE

Unchanged

Unchanged

Unchanged

DA turnover

Suppression of rhythm

Suppression of rhythm

Unchanged

Adenohypophysis

DA

Suppression of rhythm

Suppression of rhythm

Unchanged

Neurointermediate lobe

NE

Unchanged

Unchanged

Unchanged

DA

Unchanged

Unchanged

Unchanged

Pineal gland

Melatonin

Decreased

Unchanged

Decreased

NE

Unchanged

Unchanged

Unchanged

5-HT turnover

Decreased

Unchanged

Decreased

Differing from the relative compensation of circadian immune changes seen at this time of arthritis, changes in 24-h rhythms of neuroendocrine parameters persisted during the clinical phase of the disease (Garcia Bonacho, Esquifino, Castrillon, Reyes Toso, and Cardinali 2000).

Daily rhythms in plasma luteinizing hormone (LH), testosterone and TSH became suppressed or disrupted in arthritic rats. Concerning GH, the depressed mean values found in the preclinical phase of arthritis also persisted during the acute phase, as it was the case for the changes in catecholamine transmitter activity (Cano, Cardinali, Castrillon, Reyes Toso, and Esquifino 2001).

Twenty-four hours of variation in dopamine (DA) content were blunted in the anterior hypophysial lobe but remained unaltered in the neurointermediate lobe (Cano et al. 2001).

Disruption of endocrine circadian rhythms of plasma prolactin, insulin-like growth factor-1, LH and testosterone and of pituitary prolactin mRNA was recently reported in male Long Evans rats injected with FCA 23 days earlier (Roman, Seres, Herichova, Zeman, and Jurcovicova 2003).

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