estrogen administration has been found to increase tryptophan hydroxylase
5-HT2A mRNA levels in brain areas relevant for the control of mood, mental state and cognition (Sumner and Fink, 1998) and 5-HTT mRNA when administered for a longer period
n the other hand, estrogen treatment has also been observed to decrease mRNA related to serotonergic neurotransmission
Furthermore, acute estrogen administration decreases 5-HTT mRNA levels (Pecins-Thompson et al., 1998) and 5-HT1A mRNA levels and binding
assigning the effects of estrogen on serotonin to a homogenous functional class of stimulation or inhibition seems not to be feasible
Progesterone has been suggested to increase serotonergic neurotransmission via the regulation of the expression of serotonin-related genes and proteins
menopausal women gain less benefit from antidepressant treatments compared to women during their reproductive years
In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia
It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects
Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise
The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited
By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals
suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages
individuals with greater ESR at baseline experienced a greater drop in pain when taking LDN
LDN has been reported to reduce not only self-reported pain in that condition but also objective markers of inflammation and disease severity
Naltrexone has also shown some promise in improving disease severity in multiple sclerosis
The five most common adult malignancies (colorectal, breast, prostate, melanoma and lung cancer)
n breast cancer, the optimal regimen(s) for cytotoxicchemotherapy in recurrent/metastatic disease are still notdefined, despite over 30 years of ‘research’ and a plethora of RCTs since the original Cooper regimen was published in1969
The five most ‘chemo-sensitive’ cancers,namely testis, Hodgkin’s disease and non-Hodgkin’s lym- phoma, cervix and ovary
only 13 out of the 22 malignancies evaluated showed any improvement in 5-year survival, and theimprovement was greater than 10% in only three of those13 malignancies
the contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults is 2.3% in Australia and 2.1% in the USA
a benefit of less than 2.5% is likely to be applicable in other developed countries
Overview
The Contribution o
the benefit of cytotoxic chemotherapy may have been overestimated for cancers of oesophagus, stomach,rectum and brain.
this reflects the presentation of results as a ‘reduction in risk’ rather than asan absolute survival benefit[89,90]and by exaggerating theresponse rates by including ‘stable disease’
recent
studies have documented impaired cognitive function inwomen receiving adjuvant treatment for breast cancer
the 5-year survival rate due solely to cytotoxicchemotherapy was 1.6%
the value of palliative chemotherapy has beenquestioned
Incredibly low impact of cytotoxic chemotherapy despite its wide spread utilization. This article referenced cost yet did not evaluate the cost of cytotoxic side effect. The question to answer: is Cytotoxic chemotherapy a valid treatment, at all, for the majority of cancers.
Numerous in vivo and in vitro studies confirm that HBOT induces neurogenesis
HIF-1α is the principal mediator of cellular hypoxia adaptations
activated by hypoxia, HIF-1α causes the transcription of its regulated downstream genes, including erythropoietin (EPO) and VEGF which are known to promote neurogenesis
The safety of HBOT was also evaluated and it was pointed out that, if given at proper paradigms, like 1.5 ATA for 60 minutes, HBOT will not cause oxygen toxicity
Rockswold et al., on the other hand, found that HBOT might be potentially beneficial for severe TBI patients
McDonagh et al., concluded that there was insufficient evidence to establish the effectiveness of HBOT in the treatment of TBI
The first multicenter, randomized, double-blind, controlled trial in 2009 found that 40-hour HBOT of 24% oxygen at 1.3 ATM produced significant improvement in children's overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to those received slightly pressurized room air
Another study in 2010 on 16 autism patients, adopting a similar treatment paradigm, showed no effect on a wide array of behavioral evaluations
To date, there is little evidence that HBOT causes malignant growth or metastasis. A history of malignancy should therefore not be considered as a contraindication for HBOT
HBOT enhances the production of reactive oxygen species (ROS) and causes oxidative stress in body tissues
Excessive accumulation of oxidative stress may contribute to neurodegenerative processes and cell death in the brain, as seen in diseases like Alzheimer's disease (AD) and Parkinson's disease (PD)
Hormesis
process that results in a functional improvement of cellular stress resistance, survival, and longevity in response to sub-lethal levels of stress
Neurogenesis and neuroplasticity are under epigenetic control. Stress and aging downregulate adult neurogenesis; whereas physical activity, environment enrichment and learning/memory increase. Check out figure 1. Exercise increases BDNF and hence neuroplasticity. This was a synRas mouse study.
In this study, we have demonstrated microscopic pathology ranging from minimal to moderate in multiple different tissues previously reported to be involved with LD, including the nervous system (central and peripheral), heart, skeletal muscle, joint-associated tissues, and urinary bladder 12 to 13 months following tick-inoculation of rhesus macaques by Bb strain B31
Based on histomorphology, inflammation consisted predominantly of lymphocytes and plasma cells, with rare scattered histiocytes
in rare instances, morphologically intact spirochetes were observed in inflamed brain and heart tissue sections from doxycycline-treated animals
colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable
The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment
The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD
In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal
Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum
We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro
The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic
The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well
Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).
we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.
Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.
In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment
This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.
The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s
Lyme, Connecticut.
Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere
approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6
Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)
‘post-treatment Lyme disease syndrome’ (PTLDS)
host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic
inflammatory responses to residual antigens from dead organisms
residual tissue damage following pathogen clearance;
autoimmune responses, possibly elicited by antigenic mimicry
Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses
Ten male rhesus macaques
half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.
Minimal and focal lymphoplasmacytic inflammation
inflammation was observed in the leptomeninges overlying a section of temporal cerebral cortex
Minimal localized lymphoplasmacytic choroiditis
Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces
Inflammation was observed in 56% (5/9) of the NHPs irrespective of treatment group
For all animals, inflammation was reserved to perineural tissue
The treatment lasted 28 days
Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs
A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal
mild, multifocal lymphoplasmacytic inflammation was observed in one doxycycline-treated animal
three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures
10% to -20% of human patients treated
Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)
and the rapid clearance of dead spirochetes in a murine model
higher doses may be needed to combat neuroborreliosis
persistent borrelia burgdorferia were found in the brain (2) and the heart (1) up to 13 months post standard antibiotic treatment suggesting borrelia burdorferia, the cause of Lyme, can persist in a chronic, persistant state poste acute treatment.
The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
This increase was even more pronounced at 44 d, at 33%
We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial,
which occurred as early as 14 d and was maintained until the end of the trial at 44 d
We first investigated testosterone production after 24 and 48 h of ibuprofen
exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent
(β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early
as 14 d of administration
Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen
administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production
of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection
except in one experiment with DHEA
Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory
effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine
cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of
steroidogenesis.
Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence,
expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
A previous study reported
androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of
every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
the changes in gene expression indicate that the transcriptional machinery behind the endocrine action
of Leydig cells was most likely impaired by ibuprofen exposure.
Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
The decrease in the free testosterone/LH ratio resulted primarily
from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen
exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted
from ibuprofen’s direct antiandrogenic action
AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from
gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the
Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
a chemical compound, through its effects on the signaling
compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in
the adult human
The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise
response in muscles by repressing transcription
Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates
(41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes
in peritubular cells was also affected
short-term
exposure
In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated
hypogonadism (4), an entity associated with all-cause mortality
compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
an inverse relationship was recently reported between endurance exercise training and male sexual libido
AMH concentrations are lower in seminal plasma from patients with azoospermia than
from men with normal sperm levels
inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical
compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
after administration of 600 mg of ibuprofen to healthy
volunteers