kofi

In article
<b722874b-ef47-499d-a3ad-eae8c7f87ccd@x3g2000yqj.googlegroups.com>,

What I found fascinating here was the link between gut nerves in a
fairly important gut repair pathway and IGF-1 levels in the brain.
Extrapolating, it could be the case that impaired gut function/chronic
intestinal inflammation contributes to neurodegenerative disorders where
low IGF-1 is a feature. It seems that resveratrol mimics remote
ischemic preconditioning. However, resveratrol hasn't always had this
effect in experiments. I suspect this might be a dosage effect stemming
from the multiple targets of resveratrol (e.g., COX inhibition). If
there's a CGRP-mediated effect, you definitely don't want to take a
COX-2 or NOS inhibitor.

Hunger - via ghrelin - might mimic this neurogenic effect.

Also, eating too many peppers might impair this effect by ablating the
sensory nerves in the gut with a high enough dose of capsaicin. A small
dose of capsaicin - taken sporadically - might potentiate this effect.

Eur J Pharmacol. 2001 Sep 21;427(3):263-76.
*
Ischemic preconditioning, the most effective gastroprotective
intervention: involvement of prostaglandins, nitric oxide, adenosine and
sensory nerves.
Pajdo R, Brzozowski T, Konturek PC, Kwiecien S, Konturek SJ, Sliwowski
Z, Pawlik M, Ptak A, Drozdowicz D, Hahn EG.
Department of Physiology, Jagiellonian University School of Medicine, 16
Grzegorzecka St., 31-531 Cracow, Poland.

Various organs, including heart, kidneys, liver or brain, respond to
brief exposures to ischemia with an increased resistance to severe
ischemia/reperfusion and this phenomenon is called "preconditioning". No
study so far has been undertaken to check whether such short, repeated
gastric ischemic episodes protect gastric mucosa against severe damage
caused by subsequent prolonged ischemia/reperfusion and, if so, what
could be the mechanism of this phenomenon. The ischemic preconditioning
was induced by short episodes of gastric ischemia (occlusion of celiac
artery from one to five times, for 5 min each) applied 30 min before
prolonged (30 min) ischemia followed by 3 h of reperfusion or 30 min
before topical application of strong mucosal irritants, such as 100%
ethanol, 25% NaCl or 80 mM taurocholate. Exposure to regular 30-min
ischemia, followed by 3-h reperfusion, produced numerous severe gastric
lesions and significant fall in the gastric blood flow and prostaglandin
E(2) generation. Short (5-min) ischemic episodes (1-5 times) by itself
failed to cause any gastric lesions, but significantly attenuated those
produced by ischemia/reperfusion. This protection was accompanied by a
reversal of the fall in the gastric blood flow and prostaglandin E(2)
generation and resembled that induced by classic gastric mild irritants.
These protective and hyperemic effects of standard preconditioning were
significantly attenuated by pretreatment with cyclooxygenase-2 and
cyclooxygenase-1 inhibitors, such as indomethacin, Vioxx, resveratrol
and nitric oxide (NO)-synthase inhibitor, N(G)-nitro-L-arginine (L-NNA).
The protective and hyperemic effects of standard preconditioning were
restored by addition of 16,16 dm prostaglandin E(2) or L-arginine, a
substrate for NO synthase, respectively. Gastroprotective and hyperemic
actions of standard ischemic preconditioning were abolished by
pretreatment with capsaicin-inactivating sensory nerves, but restored by
the administration of exogenous CGRP to capsaicin-treated animals. Gene
and protein expression of cyclooxygenase-1, but not cyclooxygenase-2,
were detected in intact gastric mucosa and in that exposed to
ischemia/reperfusion with or without ischemic preconditioning, whereas
cyclooxygenase-2 was overexpressed only in preconditioned mucosa. We
conclude that: (1) gastric ischemic preconditioning represents one of
the most powerful protective interventions against the mucosal damage
induced by severe ischemia/reperfusion as well as by topical mucosal
irritants in the stomach; (2) gastric ischemic preconditioning resembles
the protective effect of "mild irritants" against the damage by
necrotizing substances in the stomach acting via "adaptive
cytoprotection" and involves several mediators, such as prostaglandin
derived from cyclooxygenase-1 and cyclooxygenase-2, NO originating from
NO synthase and sensory nerves that appear to play a key mechanism of
gastric ischemic preconditioning.

PMID: 11567657


Transl Res. 2009 Aug;154(2):90-102. Epub 2009 May 29
*
Stimulation of sensory neurons improves cognitive function by promoting
the hippocampal production of insulin-like growth factor-I in mice.
Harada N, Narimatsu N, Kurihara H, Nakagata N, Okajima K.
Department of Translational Medical Science Research, Nagoya City
University Graduate School of Medical Sciences, Nagoya, Japan.

Calcitonin gene-related peptide (CGRP) increases the production of
insulin-like growth factor-I (IGF-I) in the mouse brain. IGF-I exerts
beneficial effects on the cognitive function by increasing synaptic
transmission and by inducing angiogenesis and neurogenesis in the
hippocampus. In the current study, we examined whether stimulation of
sensory neurons by capsaicin improved the cognitive function by
increasing the production of IGF-I in the hippocampus using wild-type
(WT) and CGRP-knockout (CGRP-/-) mice. Significant increases of the
hippocampal tissue levels of CGRP, IGF-I, and IGF-I messenger RNA (mRNA)
were observed after capsaicin administration in WT mice (P < 0.01) but
not in CGRP-/- mice. Increase in the expression of c-fos was also
observed in the spinal dorsal horn, the parabrachial nuclei, and the
hippocampus after capsaicin administration in WT mice but not in CGRP-/-
mice. Significant enhancement of angiogenesis and neurogenesis was
observed in the dentate gyrus of the hippocampus after capsaicin
administration in WT mice (P < 0.01) but not in CGRP-/- mice. Although
capsaicin administration improved spatial learning in WT mice, no such
effect was observed in CGRP-/- mice. Capsaicin-induced improvement of
the spatial learning was reversed by administration of an anti-IGF-I
antibody and by that of a CGRP receptor antagonist CGRP (8-37) in WT
mice. The administration of IGF-I improved the spatial learning in both
WT and CGRP-/- mice. These observations strongly suggest that the
stimulation of sensory neurons by capsaicin might increase IGF-I
production via increasing the hippocampal tissue CGRP levels, and it may
thereby promote angiogenesis and neurogenesis to produce improvement of
the cognitive function in mice.

PMID: 19595440


J Pharmacol Exp Ther. 2009 Jul;330(1):2-12. Epub 2009 Mar 24
*
Donepezil improves cognitive function in mice by increasing the
production of insulin-like growth factor-I in the hippocampus.
Narimatsu N, Harada N, Kurihara H, Nakagata N, Sobue K, Okajima K.
Department of Anesthesiology and Medical Crisis Management, Nagoya City
University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan.

Insulin-like growth factor-I (IGF-I) exerts beneficial effects on
cognitive function. The selective acetylcholinesterase inhibitor
donepezil increases serum IGF-I levels in elderly subjects. Because
stimulation of sensory neurons induces IGF-I production by releasing
calcitonin gene-related peptide (CGRP) in the mouse brain, we
hypothesized that donepezil increases IGF-I production by sensory neuron
stimulation to improve the cognitive function in mice. Donepezil, but
not tacrine, increased the CGRP release from dorsal root ganglion
neurons isolated from wild-type (WT) mice. Pretreatment with the protein
kinase A inhibitor KT5720
[(9S,10S,12R)-2,3,9,10,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-
1H-diindolo[1,2,3-fg:
3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzo-diazocine-10-carboxylic acid hexyl
ester] reversed the effects induced by donepezil. Increase in tissue
levels of CGRP, IGF-I, and IGF-I mRNA in the hippocampus was observed at
4 weeks after oral administration of donepezil in WT mice. In these
animals, c-fos expression in spinal dorsal horns, parabrachial nuclei,
the solitary tract nucleus, and the hippocampus was increased.
Enhancement in angiogenesis and neurogenesis was observed in the dentate
gyrus of the hippocampus of WT mice after donepezil administration.
Improvement of spatial learning was observed in WT mice after donepezil
administration. Oral administration of tacrine for 4 weeks produced none
of the aforementioned effects induced by donepezil in WT mice. However,
none of the effects observed in WT mice was seen after donepezil
administration in CGRP-knockout mice and WT mice subjected to functional
denervation. These observations suggest that donepezil may improve
cognitive function in mice by increasing the hippocampal production of
IGF-I through sensory neuron stimulation. These effects of donepezil may
not be dependent on its acetylcholinesterase inhibitory activity.

Publication Types:
* Comparative Study

PMID: 19318594


Sensory neuropeptides modulate the mucosal response to inflammation in
experimental colitis. Because NGF regulates the expression of
neuropeptides such as substance P and calcitonin gene-related peptide
(CGRP) and is implicated as a link between the nervous system and the
immune system in the inflammatory process, we investigated the
functional role of NGF and neurotrophin-3 during experimental colitis.
METHODS: Immunoneutralizing antibodies specific for NGF and neurotrophin
(NT)-3 were used to block their endogenous activity. Mild
trinitrobenzene sulfonic acid (TNBS) colitis was induced, and damage
scores were assessed after 1 week. Neuropeptide content in the colon and
NT messenger RNA (mRNA) expression were determined. RESULTS: The
pretreatment with anti-NGF or anti-NT-3 caused a significant 2-3-fold
increase in the severity of the experimental inflammation as assessed by
a macroscopic damage score, histologic ulceration score, and
myeloperoxidase activity in the tissue. CGRP, but not substance P,
contents in the colon were significantly reduced by NGF
immunoneutralization. NGF mRNA was slightly up-regulated after NGF
immunoneutralization, but NT-3 mRNA was unchanged by NT-3
immunoneutralization. CGRP mRNA was not significantly changed after 1
week of colitis by NGF or NT-3 immunoneutralization, whereas
beta-preprotachykinin mRNA was up-regulated after immunoneutralization.
CONCLUSIONS: These findings suggest a regulatory role for NGF and NT-3
in experimental inflammation of the gut. This effect may be partly
caused by the reduction of mucosal CGRP content caused by the NGF
blockade [PMID 10930372]; Neurotrophins and GDNF have been recently
recognized as important local regulators of inflammatory processes of
the gut. RESULTS: We now demonstrate that experimental TNBS-colitis is
associated with the increased expression of neurotrophins and GDNF in
the adrenal glands. In histological sections of the adrenals from
untreated control animals, faint immunolabeling for BDNF, NT-3 and NGF
was detectable in the adrenal cortex, with some additional labeling for
NGF over the adrenal medulla, whereas GDNF immunolabeling was confined
to the adrenal medulla. Induction of TNBS-colitis markedly increased
NGF, BDNF, and NT-3 expression within the adrenal cortex after 8 h. NGF
declined to basal levels after 7 days. In case of BDNF and NT-3 basal
expression levels were reached after 14 days. GDNF expression was
robustly upregulated in the adrenal medulla 8 h after induction of
colitis and stayed elevated for up to 14 days. CONCLUSION: Together
these observations suggest that neurotrophins and GDNF might act as
local modulators of components of the HPA-axis during peripheral
inflammation [PMID 11781545]

ghrelin is a novel growth hormone (GH)-releasing, anti-inflammatory and
orexigenic peptide; 15 patients with ulcerative colitis (UC) showed
significant upregulation of mRNA for ghrelin (perhaps as a protective
response) and TNF-alpha in colonic mucosa compared to 15 healthy
controls; expression of ghrelin correlated with the grade of
inflammation and expression of TNF-alpha; in a study of trinitrobenze
sulphonic acid (TNBS)-induced colitis in rats, exogenous ghrelin (20
microg/kg i.p.) significantly accelerated the healing; iNOS mRNA and
COX-2 protein increased in colonic mucosa; TBNS downregulated protein
expression for PPARgamma in rat colonic mucosa, which was not
significantly influenced by ghrelin; rats with capsaicin-induced
functional ablation of sensory nerves revealed that exogenous ghrelin
accelerates healing of colonic lesions in rats via increased release of
NO and PGE2 due to an increase in iNOS and COX-2 expression and
stimulation of sensory neuropeptides such as CGRP released from sensory
afferent endings [PMID 19617644]

BMP-7 in culture enhances CGRP expression [PMID 17628501]

ghrelin, identified in oxyntic mucosa, controls food intake and growth
hormone (GH) release; int****ritoneal (i.p.) and intracerebroventricular
(i.c.v.) ghrelin was administered to rats given a gastric fistula (GF)
and gastric lesions induced by 75% ethanol and ischemia-reperfusion
(I/R) with or without vagotomy or functional ablation of afferent
sensory nerves by capsaicin; ghrelin increased gastric acid secretion
and attenuated gastric lesions induced by ethanol and I/R, gastric
mucosal blood flow (GBF) rose along with plasma ghrelin and gastrin
levels (gastric acid secretion); ghrelin significantly attenuated the
gastric mucosal damage and significantly raised the GBF; ethanol applied
i.g. in smaller concentrations (12.5% and 25%) produced a significant
increase in plasma ghrelin but this effect was inhibited by higher
concentrations of ethanol (75% and 100%); ghrelin¹s protection and
accompanying increase in the GBF were completely abolished by vagotomy
and capsaicin-deactivation of sensory nerves; CGRP added to ghrelin
restored the gastroprotective and hyperemic effects of ghrelin in rats
with capsaicin denervation; central and peripheral ghrelin exerts a
potent protective and gastric secretory effects in rats exposed to
ethanol and I/R, and these actions involve vagal nerve integrity,
partially depending upon afferent nerves and hyperemia mediated by
sensory neuropeptides such as CGRP released from these nerves [PMID
17228088]

orexin-A is produced by a small population of nerves in the lateral and
posterior hypothalamus; orexins strongly excite various neurons to
affect wakefulness via dopamine, norepinephrine, histamine and
acetylcholine systems; orexin-A deficit causes narcolepsy (uncontrolled
sleepiness); glucose inhibits a particular class of glucose-sensing
neurons which produce orexins; orexin-A (hypocretin-1) is found in the
neurons and endocrine cells in the gut; it controls food intake, sleep
behavior, gastric secretion and mucosal integrity; gastric secretion was
impaired and gastric lesions induced in rats by 3.5 h of water immersion
and restraint stress (WRS) or 75% ethanol; orexin-A (5-80 microg/kg
i.p.) increased gastric acid secretion and attenuated gastric lesions
induced by WRS and this was accompanied by the significant rise in
plasma orexin-A, CGRP and gastrin levels, the gastric mucosal blood flow
(GBF), luminal nitric oxide (NO) concentration and an increase in mRNA
for CGRP, overexpression of COX-2 protein and the generation of PGE2 in
the gastric mucosa; orexin-A-induced protection was abolished by
selective COX-1 receptor antagonist, vagotomy and attenuated by
suppression of COX-1 and COX-2, deactivation of afferent nerves with
neurotoxic dose of capsaicin, pretreatment with CCK(2)/gastrin
antagonist, CGRP(8-37) or capsazepine and by inhibition of NOS with
L-NNA; orexin-A has potent gastro-protective action in rats exposed to
non-topical ulcerogens like WRS or topical noxious agents like ethanol;
these effects depend upon hyperemia mediated by COX-PG and NOS-NO
systems, activation of vagal nerves and sensory neuropeptides like CGRP
released from sensory nerves probably triggered by an increase in
gastric acid secretion induced by this peptide [PMID 18378017]

serosal application of acetic acid in rats induces a gastric ulcer,
local mucosal necrosis, a reduction in mucosal microcirculation and
almost immediate expression of inducible nitric oxide (NO) synthase
(iNOS) and proinflammatory cytokines; daily application of melatonin (20
mg/kg) or l-tryptophan (100 mg/kg) accelerates ulcer healing by
affecting the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system with
excessive production of protective PG, especially in the later period of
ulcer healing; expression of hypoxia inducible factor (HIF), VEGF, an
activation of cNOS-NO system and the stimulation of sensory nerves with
the expression and release of CGRP appear to aid the restoration of
mucosal repair and microcirculation in the ulcer bed; enhanced
expression of the melatonin MT(2) receptors (MT(2)-R) combined with
overexpression of key enzymes involved in biosynthesis of melatonin such
as N-acetyltransferase and hydroxyindole-O-methyltransferase contribute
to the acceleration of ulcer healing by this indole; melatonin-induced
acceleration of ulcer healing is also mediated by release of gastrin and
ghrelin, the most potent stimulants of gastric mucosal cell
proliferation and mucosal repair; these sequential steps in ulcer
healing accelerated by melatonin can be interfered with by the blockade
of MT(2)R, COX-2/PG and cNOS/NO systems, and by reduction in the
inflammatory iNOS/NO system; melatonin and its precursor l-tryptophan,
trigger the cascade of molecular events leading to the functional
improvement in ulcer healing [PMID 18298459]; in male Wistar rats,
capsaicin-inactivation of sensory nerves (ablation) magnified gastric
mucosal damage induced by the WRS; gastric mucosal levels of
malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE; a lipid peroxidation
marker) rose and superoxide dismutase (SOD) activity dropped;
pentoxyfilline-induced gastroprotection and hyperemia depends upon
attenuation of the oxidative stress; this protection and hyperemia were,
at least in part, attenuated by ASA [PMID 17901591]

1-Methylnicotinamide (MNA), a major derivative of nicotinamide, has
antithrombotic and antiinflammatory actions; exogenous MNA was studied
on gastric secretion and gastric lesions induced in rats by 3.5 h of
water immersion and water restraint stress (WRS) or in rats administered
75% ethanol; MNA [6.25-100 mg/kg intragastrically (i.g.)] caused a
dose-dependent rise in the plasma MNA level, inhibited gastric acid
secretion, and attenuated these gastric lesions induced by WRS or
ethanol. The gastroprotective effect of MNA was accompanied by an
increase in the gastric mucosal blood flow and plasma CGRP levels, the
preservation of prostacyclin (PGI(2)) generation (measured as
6-keto-PGF1alpha), and an overexpression of mRNAs for cyclooxygenase
COX-2 and CGRP in the gastric mucosa; RO 324479, a selective antagonist
of IP/PGI(2) receptors, reversed the effects of MNA on gastric lesions
and GBF; MNA-induced gastroprotection was attenuated by suppression of
COX-1 [SC-560] and COX-2 [rofecoxib] activity, capsaicin denervation,
and by the pretreatment with CGRP(8-37) or capsazepine; exogenous PGI(2)
or CGRP restored the MNA-induced gastroprotection in rats treated with
COX-1 and COX-2 inhibitors or in those with capsaicin denervation; WRS
enhanced MDA content while decreasing SOD activity in the gastric
mucosa, but pretreatment with MNA reversed these changes; MNA exerts
potent gastroprotection against WRS damage via mechanisms involving
cooperative action of PGI(2) and CGRP in preservation of microvascular
flow, antioxidizing enzyme SOD activity, and reduction in lipid
peroxidation [PMID 18385449]

Nociceptive pathways with first-order neurons located in the trigeminal
ganglion (TG) provide sensory innervation to the head, and are
responsible for a number of common chronic pain conditions, including
migraines, temporomandibular disorders and trigeminal neuralgias. Many
of those conditions are associated with inflammation. Yet, the
mechanisms of chronic inflammatory pain remain poorly understood. Our
previous studies show that the neurotrophin brain-derived neurotrophic
factor (BDNF) is expressed by adult rat TG neurons, and released from
cultured newborn rat TG neurons by electrical stimulation and calcitonin
gene-related peptide (CGRP), a well-established mediator of trigeminal
inflammatory pain. These data suggest that BDNF plays a role in
activity-dependent plasticity at first-order trigeminal synapses,
including functional changes that take place in trigeminal nociceptive
pathways during chronic inflammation. The present study was designed to
determine the effects of peripheral inflammation, using tooth pulp
inflammation as a model, on regulation of BDNF expression in TG neurons
of juvenile rats and mice. Cavities were prepared in right-side
maxillary first and second molars of 4-week-old animals, and left open
to oral microflora. BDNF expression in right TG was compared with
contralateral TG of the same animal, and with right TG of sham-operated
controls, 7 and 28 days after cavity preparation. Our ELISA data
indicate that exposing the tooth pulp for 28 days, with confirmed
inflammation, leads to a significant upregulation of BDNF in the TG
ipsilateral to the affected teeth. Double-immunohistochemistry with
antibodies against BDNF combined with one of nociceptor markers, CGRP or
transient receptor potential vanilloid type 1 (TRPV1), revealed that
BDNF is significantly upregulated in TRPV1-immunoreactive (IR) neurons
in both rats and mice, and CGRP-IR neurons in mice, but not rats.
Overall, the inflammation-induced upregulation of BDNF is stronger in
mice compared to rats. Thus, mouse TG provides a suitable model to study
molecular mechanisms of inflammation-dependent regulation of BDNF
expression in vivo [PMID 20223282]