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Abstract

This paper addresses how hormesis, a biphasic dose response, can protect and affect performance of neural systems. Particular attention is directed to the potential role of hormesis in mitigating age-related neurodegenerative diseases, genetically based neurological diseases, as well as stroke, traumatic brain injury, seizure, and stress-related conditions. The hormetic dose response is of particular significance since it mediates the magnitude and range of neuroprotective processes. Consideration of hormetic dose-response concepts can also enhance the quality of study designs, including sample size/statistical power strategies, selection of treatment groups, dose spacing, and temporal/repeat measures’ features.
© 2017 Brain Circulation | Published by Wolters Kluwer Health – Medknow 1
The role of hormesis in the functional
performance and protection of neural
systems
Edward J Calabrese, Vittorio Calabrese1, James Giordano2
Abstract:
This paper addresses how hormesis, a biphasic dose response, can protect and affect performance
of neural systems. Particular attention is directed to the potential role of hormesis in mitigating
age‑related neurodegenerative diseases, genetically based neurological diseases, as well as
stroke, traumatic brain injury, seizure, and stress‑related conditions. The hormetic dose response is
of particular signicance since it mediates the magnitude and range of neuroprotective processes.
Consideration of hormetic dose‑response concepts can also enhance the quality of study designs,
including sample size/statistical power strategies, selection of treatment groups, dose spacing, and
temporal/repeat measures’ features.
Keywords:
Biphasicdose response, hormesis, hormetic dose response, neuroprotection, postconditioning,
preconditioning
Introduction
Ongoing neuroscientific research
is focused on preventing and/or
reducing the occurrence and extent of
neuropsychiatric disease and neurological
injury-based processes/events, mitigating
age-related decrements in neurocognitive
performance and improving defined
aspects of cognitive performance in healthy
individuals. These research domains share
a grounding impetus to access, assess, and
affect the nervous system in attempts to
enhance health and performance throughout
the lifespan.
Achieving these key ends remains somewhat
problematic, given the diversity of functions,
substrates, and mechanisms putatively
involved, and the defined limitations of
extant approaches commonly employed.
When assessing gaps in such approaches,
it
becomes apparent that a common goal would
be to achieve an optimal biological response
that evokes desired effects in a number
of neurological substrates and processes.
To date, most interventions have been
characteristically engaged and evaluated
within a dose-response context that is
considered to enable the pharmacokinetic and
pharmacodynamic effects desired. However,
it is becoming clear that such dose-response
parameters may be less than optimal in
exploiting the amplication mechanisms of
the nervous system,[1] and thus may tend
to produce unwanted, or in some cases
adverse effects, while in other cases, may
appear to be ineffective (due to paradoxical
actions). In light of this, we propose that
response optimization can positively affect
neurobiological functions toward evoking a
variety of desirable end points and that such
effects are both dened and mediated by
hormesis. This paper assesses the concept of
hormetic dose responses, the occurrence and
Address for
correspondence:
Prof. Edward J Calabrese,
School of Public Health
and Health Sciences,
Environmental Health
Sciences, Morrill I,
N344, University of
Massachusetts, Amherst,
MA 01003, USA.
E-mail: edwardc@
schoolph.umass.edu
Submission: 30-09-2016
Revised: 06-12-2016
Accepted: 13-12-2016
Department of
Environmental Health
Sciences, School of
Public Health and
Health Sciences, Morrill
I, N344, University of
Massachusetts, Amherst,
MA 01003, 2Department
of Neurology and
Biochemistry, Georgetown
University Medical Center,
Washington, DC 20057,
USA, 1Department
of Biomedical and
Biotechnological Sciences,
School of Medicine,
University of Catania,
Viale Andrea Doria,
Catania, Italy
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DOI:
10.4103/2394-8108.203257
How to cite this article: Calabrese EJ, Calabrese V,
Giordano J. The role of hormesis in the functional
performance and protection of neural systems. Brain
Circ 2017;3:1-13.
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Calabrese, et al.: Hormesis and neuroprotection
2 Brain Circulation - Volume 3, Issue 1, January-March 2017
signicance of these processes in and to the protection and
functional optimization of neurological systems, and the
putative molecular and cellular mechanisms subserving
such responses and effects.
Hormesis: A Historical Overview
The term hormesis, originating from the Greek “to excite,”
was first introduced into the biomedical lexicon by
Southam and Ehrlich[2] to describe the effects of extracts
of the Red Cedar tree on wood-rotting fungi. These
investigators found that several species of fungi display
a low-dose stimulation and a high-dose inhibition for cell
metabolism and survival. Southam and Ehrlich were aware
of historically old descriptions of this type of biphasic dose
response, with reports dating from the 1880s by Schulz,[3,4]
who assessed the effects of multiple disinfectants on
yeast metabolism and survival. By the 20th century, such
research became increasingly more widespread, especially
in microbiology and botany, wherein the biphasic dose
response was seen as a general biological phenomenon.
Detailed summarization and overview of the historicity
and canonical development and dissemination of hormesis
research is provided by Calabrese and Baldwin,[5-9] and
Calabrese[10] also provides an assessment of controversies
and challenges surrounding the validity, viability, and
value of this dose-response model within the conventional
biological and medical paradigms.
Despite such challenges and controversies, what has
become clear is that hormesis represents a biphasic dose
response that occurs following either direct stimulation by
a chemical or physical agent or as an overcompensatory
response to toxic or homeostatically disruptive insult.[11]
Regardless of how the hormetic dose response is induced,
its quantitative features (i.e., amplitude and width of the
stimulation) are similar[12,13] and appear to be independent
of mechanism. Furthermore, the highly generalizable
amplitude of hormetic stimulation suggests that the
quantitative features of the hormetic dose response may
be a measure of biological plasticity, which reects the
relative “gain” of the system affected.[14] Quantitative
evaluations indicate that hormetic stimulation conforms
to an allometrically estimable parameter.[14,15] In this light,
hormetic dose responses can be seen as evolutionarily
based, adaptive, and highly generalizable,[16] reecting
a biological process of optimizing and managing the
use of cellular resources under a variety of temporal,
environmental, and stress-related conditions and effects.[17]
Hormesis and Preconditioning: A Role in
Neuroprotection
First reports in the biomedical literature
While it has been over 130 years since Schulz made his
rst presentation on hormesis to the Greifswald Medical
Society in 1884,[18] the rst report associating hormesis
with neuroprotection appeared in the biomedical
literature in 1999; Jonas et al.[19] described how a prior low
dose of glutamate may protect against subsequent higher
and toxic doses of glutamate in a preconditioning (PC)
experiment. Hormetic neuroprotection was subsequently
reported by Andoh et al.[20] [Table 1].
Initial correlation of PC to neuroprotection appeared in
the biomedical literature in the journal Neuroscience, in a
study examining HSP70 synthesis in ischemic tolerance
induced by PC effects in the rat hippocampus.[15] This
paper preceded by 15 years the publication of Calabrese
et al.[21] which integrated the concept of PC with hormesis,
and proposed a common set of terms to describe
biological stress responses within hormetic contexts.
Despite the fact that a role for hormesis in neuroprotection
has explicitly emerged within the research community
within the past two decades, review of PubMed/Web
of Science listings (i.e., for hormesis) revealed that
the historical study of hormesis and the possibility
of hormetic PC to affect neurological function had
heretofore not been well depicted and fully recognized
in the neuroscientic literature [Table 1]. For example,
while there are >1700 citations in the Web of Science
for PC and neuroprotection, there are only 40 citations
for hormesis and neuroprotection, regardless of the
evolving appreciation that PC is a manifestation of
hormesis.[22-24] This lack of recognition, and a failure to
integrate the hormesis concept into the neuroscientic/
neuroprotection literature, appears to be due to
many factors, including, but not limited to a lack of
understanding of the quantitative aspects of hormetic
dose-response features that persisted until the late
1990s,[25-28] the use of multiple terms to describe
hormetic dose responses (e.g., biphasic, U-shaped,
J-shaped, Arndt-Schulz Law, Hueppe’s Rule, bitonic,
hormoligosis, rebound effect, repeat bout effect, etc.),
lack of mechanistic understanding,[29] difficulty in
assessment and replication of hormetic effects due to the
modest nature of the low dose stimulatory response, and
lack of strategy in end point selection.
A role for hormesis in the performance and
protection of neurobiological systems
Neurobiological performance and neuroprotection
mediated by hormetic mechanisms and manifested
within the framework of hormetic-biphasic
dose-response relationships were the foci of a thematic
issue of Critical Reviews in Toxicology in 2008.[30] This
issue included 14 papers devoted to diverse areas of
neuroscience, in which hormetic dose responses were
observed to play a signicant role in reducing damage
during normal aging,[30,31] slowing the onset of major
neurodegenerative diseases (e.g., Alzheimer’s disease,
Calabrese, et al.: Hormesis and neuroprotection
Brain Circulation - Volume 3, Issue 1, January-March 2017 3
Parkinson’s disease, Huntington’s disease, etc.),[31-33]
and reducing damage from stroke and traumatic brain
injury.[34] Hormetic effects were also shown to facilitate
neurite outgrowth,[35] modulate pain,[36] mediate stress
responses,[37] and enhance adaptive responses in
astrocytes.[38] Hormetic responses were extensively
observed in studies assessing pharmacological
interventions to enhance memory,[33] decrease anxiety,[39]
prevent seizure onset, and reduce seizure severity.[40]
Each of these papers was subjected to independent
evaluations and critiques.[41-45]
These papers demonstrated the occurrence and
commonality of hormetic responses in neurological
systems and extended the generality of hormetic dose
responses to neuroprotective processes at molecular,
cellular, and organismal levels of biological organization.
The analyses indicated that quantitative features of the
adaptive/protective responses in neuroprotection studies
were similar, regardless of end point measured, biological
model, mechanism, therapeutic agent employed, or
disease process(es) studied.[29,46] Of particular interest
was the demonstration that hormetic-like biphasic
dose-response relationships in neurobiological systems
had been reported in the literature for nearly a century[47]
without recognition that such dose responses were
similar to those reported in other elds of the biological
sciences, and without placing such ndings in broader
neuroscientic context.
As potentially novel as these findings of hormetic
responses were for neuroscience, it is important to
note that they were in fact wholly consistent with the
existing and rather extensive literature demonstrating
hormesis in other domains of the biological sciences.
[5-9,12,13,48-52] For example, decades prior to the 2008
Critical Reviews in Toxicology issue on neuroscience and
hormesis, a German language journal, Cell Stimulation
Research (Zell Stimulations‑Forschungen, 1924–1930)[53]
published ndings on hormesis during the 1920s, and
reports of hormesis were also provided in a journal-like
publication, the Stimulation Newsletter.[54] Luckey[55,56]
published two books that provided considerable
documentation of ionizing radiation-induced hormesis
within a variety of biological models. Likewise,
Stebbing[57-59] published substantial research addressing
toxicology and hormesis, with particular emphasis on
effects in the marine environment.
The rst conference addressing hormesis was held in
August 1985 in Oakland, California, with peer-reviewed
proceedings published in the journal Health Physics
2 years later. Subsequently, Calabrese extended these
efforts and conducted a series of conferences, which
began in the 1990s[60-62] and which continue to the
present. These meetings convene an international
cadre of researchers who have studied, assessed, and
documented evidence demonstrating hormesis in
immunologic systems,[63] tumor cell biology,[64] mediating
Table 1: The historical listing of hormesis and neuroscience and hormesis and neuroprotection in PubMed and
web of science
Hormesis and Neuroscience
Arumugam TV, Gleichmann M, Tang SC, Mattson MP. 2006. Hormesis/preconditioning mechanisms, the nervous system and aging. Ageing
Res Rev. 5(2):165‑78.
Mattson MP, Duan W, Chan SL, Cheng A, Haughey N, Gary DS, Guo Z, Lee J, Furukawa K. 2002. Neuroprotective and neurorestorative
signal transduction mechanisms in brain aging: modication by genes, diet and behavior. Neurobiol Aging 23(5):695-705.
Mattson MP, Chan SL, Duan W. 2002. Modication of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol
Rev. 82(3):637-72.
Hormesis and Neuroprotection
*Andoh T, Chock PB, Chiueh CC. 2002. The roles of thioredoxin in protection against oxidative stress‑induced apoptosis in SH‑SY5Y cells.J
Biol Chem. 22;277(12):9655-60.
Jonas, W; Lin, Y; Tortella, F. 2001. Neuroprotection from glutamate toxicity with ultra-low dose glutamate. NeuroReport 12(2): 335-339.
Jonas, W; Lin, Y; Williams, A; et al. 1999. Treatment of experimental stroke with low-dose glutamate and homeopathic Arnica montana.
Perfusion 12(11): 452‑+
Preconditioning and Neuroprotection/Neuroscience
Chen J, Graham SH, Zhu RL, Simon RP. 1996. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab.
16(4):566‑577.
Gage AT, Stanton PK. 1996. Hypoxia triggers neuroprotective alterations in hippocampal gene expression via a heme-containing sensor.
Brain Res. 719(1-2):172-178.
Matsushima K, Hakim AM. 1995. Transient forebrain ischemia protects against subsequent focal cerebral ischemia without changing
cerebral perfusion. Stroke 26(6):1047‑1052.
Gidday JM, Fitzgibbons JC, Shah AR, Park TS. 1994. Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal
rat. Neurosci Lett. 168(1‑2):221‑224.
Liu Y, Kato H, Nakata N, Kogure K. 1993. Temporal prole of heat shock protein 70 synthesis in ischemic tolerance induced by
preconditioning ischemia in rat hippocampus.
Neuroscience. 56(4):921-927.
*First paper that linked hormesis, preconditioning and neuroprotection
Calabrese, et al.: Hormesis and neuroprotection
4 Brain Circulation - Volume 3, Issue 1, January-March 2017
effects of pharmacological interventions inclusive of
adrenergic agents,[65] prostaglandins,[66] xanthines,[67]
nitric oxide,[68] serotonin (5-hydroxytryptamine),[69]
opioids,[70] dopamine,[71] estrogens,[72] androgens,[73] as
well as heavy metals[74] and mediating apoptosis.[75]
Following this consolidation of information, Calabrese
et al.[21] proposed that biological stress terminology,
including the concepts of pre- and post-conditioning,
be incorporated within a hormetic framework. These
developments may provide a scientic foundation upon
which to structure the integration of new ndings on
hormesis and pre- and post-conditioning to the current
and future knowledge of processes and mechanisms of
neuroprotection,[12] and to enable greater understanding
of frequency and temporal aspects of hormetic-biphasic
dose-response relationships in neural systems.[76-82]
Hormetic dose-response effects appear to be involved in
the action of pharmacological agents that have been shown
to enhance social interactions,[39] decrease anxiety,[39]
reduce pain,[36] and enhance memory[33] [Figure 1].
In this latter regard, it is noteworthy that all drugs
currently approved by the United States Food and Drug
Administration to relieve symptoms of Alzheimer’s
disease and to reduce seizures have been shown to
display hormetic dose responses during preclinical
phases of testing in animal models.[33,40]
Hormetic responses in these models do not constitute
neuroprotection per se, but increasing certain aspects of
neural function can and frequently does exert inuence
upon neuroprotective mechanisms and effects. For
example, if neural mechanisms are impaired (e.g., via
aging processes, genetic predisposition, injury, etc.), it is
likely that a decrement in the performance of particular
cognitive and/or behavioral capabilities and tasks will
result. Pre- and/or post-conditioning processes may
provide some modicum of protection against these
insults and effects. Conversely, if and when these
functions are maintained and/or facilitated in a healthy
individual, such effects would be considered to be a type
of neurological performance optimization.[83] This is not
merely semantics; rather, terms and denitions used
and their meanings employed in medical, social, and
legal contexts are important to establishing standards
and guidelines that can inuence, if not direct, research
agenda and the relative view and value of research
outcomes for translational use in practice.[84-86]
An experimental approach to assessing hormesis
The assessment of hormesis in experimental contexts
can be challenging given that the magnitude of the
low-dose stimulation is modest, typically being only
30%–60% greater than the control group.[12] This
biphasic dose response is also temporally dependent,
making the hormetic response a dose-time response.
This necessitates conducting experiments to assess
an adequate dose-range within a repeated measures
experimental design. It also requires strong statistical
power and appropriate experimental replication.
Knowledge of control group variation is extremely
important when assessing hormetic dose responses.
The use of a control group with low variability is
critical to the protocol. These factors are essential for
creating the necessary conditions in which hypotheses
regarding hormetic dose-response effects can and
should be effectively tested and evaluated.
These experimental parameters have important
implications for many types of low-dose assessments.
For example, they may place specic constraints on
high throughput studies that utilize thousands of
compounds. Such a range of compounds may have
a wide spectrum of physiochemical properties that
differentially affect the uptake and action of ligands
at particular subcellular substrates, which could then
Neuroperformance/Protection and Hormesis
Memory General Biological
Performance –
Numerous Functions
Anxiety
Disorders
Seizure
Pain
Control
Normal
Individual
Alzheimer’s
disease
Optimal
Stress
Foundation of Yerkes-
Dodson Law
TBI
Stroke
Glaucoma
Hearing Loss
Figure 1: Partial listing of neuroperformance/protection domains affected by hormesis
Calabrese, et al.: Hormesis and neuroprotection
Brain Circulation - Volume 3, Issue 1, January-March 2017 5
elicit physiological effects and outcomes at a variety of
levels within a biological system. Since high throughput
systems often test compounds at only one-time point,
hormetic dose responses can be masked. Further,
hormetic evaluations typically entail the requirement to
rst estimate a threshold response so that subthreshold
doses can be tested in subsequent evaluations, and this
needs to be considered (and implemented) in any/all
research that aims to assess putative hormetic effects.
An example of a study design that effectively
evaluated several hormetic hypotheses is provided
by Zhang et al.,[87] whose research studied both direct
stimulation-induced hormesis and the relation of
hormetic responses to PC effects. As shown in Figure 2,
Zhang et al.[87] presented effects of camptothecin (CPT)
on PC12 cells (a rat pheochromocytoma cell line,
which produces dopamine and exhibits characteristics
that are consistent with neuronal cells), across 11
concentrations (i.e., 1400-fold concentration range).
CPT is a monoterpene indole alkaloid that inhibits
a topoisomerase-1 by stabilizing the enzyme-DNA
complex. Topoisomerases are enzymes that affect
supercoiling during the DNA replication process.
These studies revealed a hormetic biphasic dose
response with a maximum stimulation of ~40%, and
a stimulatory range of ~44-fold (0.01–0.44 uM). After
completing and replicating the experiment, the authors
then evaluated CPT within a PC protocol in which CPT
was administered 24 h before an oxidizing challenge
induced by perfusion with hydrogen peroxide (H2O2).
Of note was that H2O2 diminished the response of the
control group and each of the four treatment groups
in a manner that was approximately proportional to
the response seen in the direct stimulatory experiment.
Thus, although the PC treatment was not able to fully
protect the PC12 (i.e., prevent any decrease from the
original control group values), it did incur an increase
in response that was 40% greater than that seen in
the (H2O2-treated) control group.
Zhang et al.[87] additionally addressed the mechanism(s)
by which CPT enhances the viability of PC12 cells via
direct stimulation and/or PC. Low concentrations
of CPT enhanced cell proliferation by upregulating
p-P13k, p-AKT, and p-mTOR, as well as the expression
of several proteins, including HO-1 and Nrf2. CPT
also downregulated PTEN expression. These ndings
strengthen the hypothesis that the hormetic and
neuroprotective effects of low concentrations of CPT
in PC12 cells occurred via upregulation of P13k/AKT/
mTOR and Nrf2/HO-1 pathways. The capacity of CPT
to enhance MTT at low concentrations was also shown,
suggesting a putative role for mitochondrial metabolism
in the hormetic process. The administration of the P13
inhibitor, LY294002, blocked the low-dose stimulation,
further suggesting that the P13k pathway is involved in
hormetic and neuroprotective effects of CPT in PC12 cells.
Figure 3(a-y) provides several examples of hormetic
dose responses in neurobiological models. These
examples were selected to illustrate the range, diversity,
and generality of the hormetic dose-response in
neural systems. As well, these examples illustrate
the generally consistent quantitative features of the
hormetic dose response, which is especially evident
with respect to the amplitude of response. In some cases,
detailed mechanistic ndings are represented and/or
summarized in the gures, as related to either specic
receptors and/or cell signaling pathways that have been
shown to mediate the hormetic response.
Support for Hormetic Effects in Neural
Systems: The Hormesis Data Base
Within the hormesis data base,[13] there are almost
three hundred entries for hormetic dose-response
Figure 2: Effects of camptothecin on PC12 cell viability using direct stimulation and
preconditioning protocols (adapted from: Zhang et al.)[87]
Figure 3(a): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Calabrese, et al.: Hormesis and neuroprotection
6 Brain Circulation - Volume 3, Issue 1, January-March 2017
effects in neural systems and models. Assessment
of these entries reveals that ~87% were from in vitro
studies, and ~13% were from in vivo studies. Of these
studies, 80% have >3 doses below the zero equivalent
Figure 3(b): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(c): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(d): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(e): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(f): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(g): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Calabrese, et al.: Hormesis and neuroprotection
Brain Circulation - Volume 3, Issue 1, January-March 2017 7
point (ZEP) (i.e., threshold), and 42.5% have >5 doses
below the ZEP [Figure 4]. Consistent with other end
points (i.e., as shown in non-neurobiologically based
studies), <20% of the dose responses in neurobiological
Figure 3(h): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(i): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(j): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(k): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(l): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(m): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Calabrese, et al.: Hormesis and neuroprotection
8 Brain Circulation - Volume 3, Issue 1, January-March 2017
systems exhibited maximum response in an inverted
U-shaped dose response that was greater than twice
the control group value, while approximately 80% had
a maximum response between 10% and 100% greater
Figure 3(n): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
0
25
50
75
100
125
150
175
200
01310 30 10
03
00
R(+)-WIN 55212-2 (nM)
Viability (% Control)
The Effects of R(+)-WIN 55212-2, a Synthetic Cannabinoid
Agonist, on the Viability of Cultured Cerebral Cortical
Neurons from Male Sprague-Dawley Rats
Protection blocked by the CB1
receptor antagonist
SR141716A
Figure 3(o): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(r): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112] Figure 3(s): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(p): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112] Figure 3(q): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Calabrese, et al.: Hormesis and neuroprotection
Brain Circulation - Volume 3, Issue 1, January-March 2017 9
than the control group [Figure 5]. While nearly 85% of the
in vivo studies displayed a width of stimulation within
0
25
50
75
100
125
150
175
200
% Control
µ-Thrombin (nM)
******
*
**
**
Effects of µ-Thrombin Thymidine Icorproation Into
DNA on C6 Rat Glioma Cells
Thrombin receptor antagonist
peptide T1 blocked the inhibitory
effect but had no effect on
stimulation
Figure 3(t): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(u): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(v): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(w): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(x): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
Figure 3(y): Examples of neuroprotective effects displaying hormetic dose
responses
[89‑112]
100-fold of the ZEP, this was the case for only 52.6%
for the in vitro studies, with 21% of these displaying a
Calabrese, et al.: Hormesis and neuroprotection
10 Brain Circulation - Volume 3, Issue 1, January-March 2017
lack more complex biological regulatory controls or
may be an issue related to the limited sample size in
the in vivo studies. Hormetic dose responses have been
shown in a variety of neural systems and models (e.g. a
range of PC12, MN9D cells [a dopamine neuron model],
HT-22 cells [mouse hippocampal cells], rat glioma cells,
and RBE-4 [rat brain endothelial cells]) [Figure 3]. To
reiterate, these ndings indicate that hormetic dose
responses in neural systems display quantitative
characteristics that are similar to those occurring in
other biological models and end points, suggesting
that hormetic responses may be a broad, general
physiologically adaptive process.
Discussion
Hormetic dose responses occur in a number of neural
systems and models. We posit that such hormetic
effects sustain the function of neurological systems
under normal conditions, fortify and optimize certain
neural functions, and when taken together, may serve
to protect neural systems (viz., the brain) from a variety
of metabolic, neurodegenerative and traumatic insults.
In neural systems (as in other biological systems), the
hormetic response is constrained by limits of plasticity
which, in turn, reect the quantitative features of the
hormetic dose response. These ndings suggest that the
hormetic dose response likely plays a fundamental role
in neural performance and neuroprotection, which may
be applicable and of value in experimental and clinical
contexts.
In general, the most signicant and consistent observation
of hormetic dose responses is that the magnitude of
the stimulation/protective effect is modest, being at
maximum only 30%–60% greater than the control
group. While this response denes, and perhaps restricts
potential benefit, it also reveals that demonstrating
benecial effects in highly heterogeneous experimental
treatment groups may be challenging. In this light, it is
equally important to note that there is little evidence to
suggest that experimental approaches using simultaneous
multiple treatments (e.g., pharmacological/mechanical,
etc.) and/or specific temporal sequence treatment
approaches will impart improvements that exceed this
30%–60% maximum protective response.[33] However,
while it may be difficult to exceed the apparent
bounds of biological plasticity, some success has been
achieved in extending the period of protection from
days to a few months via manipulation of PC methods
employed.[88] Thus, it will be important to direct current
and future research to nd reliable and practical ways
to achieve protection >30%–60%, to reliably extend the
neuroprotection period, and to more fully dene and
detail mechanisms and effects of hormetic responses in
neural systems.
Figure 4: Percentage Of Neuroscience Dose‑Response Experiments In The
Hormetic Database With A Specic Number Of Doses Below The Zero Equivalent
Point
Figure 5: Percentage of total neuroscience dose‑response experiments within a
specic maximum stimulatory response range in the hormetic database
Figure 6: Dose‑response relationships by width of stimulation range in
neuroscience experiments in the hormetic database
stimulating width of >1000-fold [Figure 6]. This marked
contrast may be an artifact of in vitro studies, which
Calabrese, et al.: Hormesis and neuroprotection
Brain Circulation - Volume 3, Issue 1, January-March 2017 11
Acknowledgments
The prior work on hormesis by EC that has provided
the basis for much of the information contained in this
manuscript has been supported by the United States
Air Force and ExxonMobil Foundation. The views and
conclusions contained herein are those of the authors
and should not be interpreted as necessarily representing
those of supporting organizations, or as representative
of expressed or implied endorsements or policies.
Financial support and sponsorship
The present work was supported, in part, by funding
from the AEHS Foundation, the United States Air Force
Ofce of Research, and the William H and Ruth Crane
Schaefer Endowment (JG).
Conicts of interest
There are no conicts of interest.
References
1. Calabrese Ej, Ives Ja, Giordano J. Neuroprotective Agents Commonly
Display Hormesis: Implications For Nanoneuropharmacology. In:
Giordano J, Editor. Neurotechnology: Premises, Potential And
Problems. Boca Raton, Fl: Crc Press; 2012. P. 69-92.
2. Southam CM, Ehrlich J. Effects of extract of Western red-cedar
heartwood on certain wood-decaying fungi in culture.
Phytopathology 1943;33:517-24.
3. Schulz H. Zur lehre von der arzneiwirkung. Arch Pathol Anat
Physiol Klin Med 1887;108:423-45.
4. Schulz H. About yeast poisons. Arch Gesamte Physiol Menschen
Tiere 1888;42:517-41.
5. Calabrese EJ, Baldwin LA. Chemical hormesis: Its historical
foundations as a biological hypothesis. Hum Exp Toxicol
2000;19:2-31.
6. Calabrese EJ, Baldwin LA. The marginalization of hormesis. Hum
Exp Toxicol 2000;19:32-40.
7. Calabrese EJ, Baldwin LA. Radiation hormesis: Its historical
foundations as a biological hypothesis. Hum Exp Toxicol
2000;19:41-75.
8. Calabrese EJ, Baldwin LA. Radiation hormesis: The demise of a
legitimate hypothesis. Hum Exp Toxicol 2000;19:76-84.
9. Calabrese EJ, Baldwin LA. Tales of two similar hypotheses: The
rise and fall of chemical and radiation hormesis. Hum Exp Toxicol
2000;19:85-97.
10. Calabrese EJ. Getting the dose-response wrong: Why hormesis
became marginalized and the threshold model accepted. Arch
Toxicol 2009;83:227-47.
11. Calabrese EJ, Baldwin LA. Dening hormesis. Hum Exp Toxicol
2002;21:91-7.
12. Calabrese EJ, Blain R. The occurrence of hormetic dose responses
in the toxicological literature, the hormesis database: An overview.
Toxicol Appl Pharmacol 2005;202:289-301.
13. Calabrese EJ, Blain RB. The hormesis database: The occurrence
of hormetic dose responses in the toxicological literature. Regul
Toxicol Pharmacol 2011;61:73-81.
14. Calabrese EJ, Mattson MP. Hormesis provides a generalized
quantitative estimate of biological plasticity. J Cell Commun
Signal 2011;5:25-38.
15. Calabrese EJ. Biphasic dose responses in biology, toxicology and
medicine: Accounting for their generalizability and quantitative
features. Environ Pollut 2013;182:452-60.
16. Parsons PA. Radiation hormesis: An evolutionary expectation
and the evidence. Int J Rad Appl Instrum A 1990;41:857-60.
17. Calabrese EJ. Toxicology rewrites its history and rethinks its
future: Giving equal focus to both harmful and benecial effects.
Environ Toxicol Chem 2011;30:2658-73.
18. Jonas W, Lin Y, Williams A, Tortella F, Tuma R. Treatment of
experimental stroke with low-dose glutamate and homeopathic
Arnica montana. Perfusion 1999;12:452.
19. Andoh T, Chock PB, Chiueh CC. The roles of thioredoxin in
protection against oxidative stress-induced apoptosis in SH-SY5Y
cells. J Biol Chem 2002;277:9655-60.
20. Liu Y, Kato H, Nakata N, Kogure K. Temporal prole of heat
shock protein 70 synthesis in ischemic tolerance induced by
preconditioning ischemia in rat hippocampus. Neuroscience
1993;56:921-7.
21. Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J,
Cai L, et al. Biological stress response terminology: Integrating the
concepts of adaptive response and preconditioning stress within
a hormetic dose-response framework. Toxicol Appl Pharmacol
2007;222:122-8.
22. Calabrese EJ. Preconditioning is hormesis part I: Documentation,
dose-response features and mechanistic foundations. Pharmacol
Res 2016;110:242-64.
23. Calabrese EJ. Preconditioning is hormesis part II: How the
conditioning dose mediates protection: Dose optimization
within temporal and mechanistic frameworks. Pharmacol Res
2016;110:265-75.
24. Calabrese EJ. Pre- and post-conditioning hormesis in elderly
mice, rats, and humans: Its loss and restoration. Biogerontology
2016;17:681-702.
25. Calabrese EJ, Baldwin LA. The dose determines the stimulation
(and poison): Development of a chemical hormesis database. Int
J Toxicol 1997;16:545-59.
26. Calabrese EJ, Baldwin LA. A quantitatively-based methodology
for the evaluation of chemical hormesis. Hum Ecol Risk
Assessment 1997;3:545-54.
27. Calabrese EJ, Baldwin LA. A general classication of U‑shaped
dose-response relationships in toxicology and their mechanistic
foundations. Hum Exp Toxicol 1998;17:353-64.
28. Calabrese EJ, Baldwin LA. Hormesis as a biological hypothesis.
Environ Health Perspect 1998;106 Suppl 1:357-62.
29. Calabrese EJ. Hormetic mechanisms. Crit Rev Toxicol
2013;43:580-606.
30. Calabrese EJ. Neuroscience and hormesis: Overview and general
ndings. Crit Rev Toxicol 2008;38:249‑52.
31. Calabrese EJ. Dose-response features of neuroprotective agents:
An integrative summary. Crit Rev Toxicol 2008;38:253-348.
32. Calabrese EJ. Pharmacological enhancement of neuronal survival.
Crit Rev Toxicol 2008;38:349-89.
33. Calabrese EJ. Alzheimer’s disease drugs: An application
of the hormetic dose-response model. Crit Rev Toxicol
2008;38:419-51.
34. Calabrese Ej. Drug Therapies For Stroke And Traumatic Brain
Injury Often Display U-Shaped Dose Responses: Occurrence,
Mechanisms, And Clinical Implications. Crit Rev Toxicol
2008;38:557-77.
35. Calabrese EJ. Enhancing and regulating neurite outgrowth. Crit
Rev Toxicol 2008;38:391-418.
36. Calabrese EJ. Pain and U-shaped dose responses: Occurrence,
mechanisms, and clinical implications. Crit Rev Toxicol
2008;38:579-90.
37. Calabrese EJ. Stress biology and hormesis: The Yerkes-Dodson
law in psychology – a special case of the hormesis dose response.
Crit Rev Toxicol 2008;38:453-62.
38. Calabrese EJ. Astrocytes: Adaptive responses to low doses of
neurotoxins. Crit Rev Toxicol 2008;38:463-71.
Calabrese, et al.: Hormesis and neuroprotection
12 Brain Circulation - Volume 3, Issue 1, January-March 2017
39. Calabrese EJ. An assessment of anxiolytic drug screening
tests: Hormetic dose responses predominate. Crit Rev Toxicol
2008;38:489-542.
40. Calabrese EJ. Modulation of the epileptic seizure threshold:
Implications of biphasic dose responses. Crit Rev Toxicol
2008;38:543-56.
41. Diamond DM. The search for hormesis in the nervous system.
Crit Rev Toxicol 2008;38:619-22.
42. Giordano J, Ives JA, Jonas WB. Hormetic responses in neural
systems: Consideration, contexts, and caveats. Crit Rev Toxicol
2008;38:623-7.
43. Kastin AJ, Pan W. Peptides and hormesis. Crit Rev Toxicol
2008;38:629-31.
44. Mattson MP. Awareness of hormesis will enhance future
research in basic and applied neuroscience. Crit Rev Toxicol
2008;38:633-9.
45. Stark M. Hormesis, adaptation, and the sandpile model. Crit Rev
Toxicol 2008;38:641-4.
46. Calabrese EJ, Hoffmann GR, Stanek EJ, Nascarella MA. Hormesis
in high-throughput screening of antibacterial compounds in
E. coli. Hum Exp Toxicol 2010;29:667-77.
47. Yerkes RM, Dodson JD. The relation of strength of stimulus
to rapidity of habit-formation. J Comp Neurol Psychol
1908;18:459-82.
48. Calabrese EJ. Hormesis: Why it is important to toxicology and
toxicologists. Environ Toxicol Chem 2008;27:1451-74.
49. Calabrese EJ, Blain RB. Hormesis and plant biology. Environ
Pollut 2009;157:42-8.
50. Calabrese EJ, Iavicoli I, Calabrese V. Hormesis: Why it is important
to biogerontologists. Biogerontology 2012;13:215-35.
51. Calabrese EJ, Dhawan G, Kapoor R, Iavicoli I, Calabrese V. What
is hormesis and its relevance to healthy aging and longevity?
Biogerontology 2015;16:693-707.
52. Rattan SI, Le Bourg E. Hormesis in Health and Disease. Boca
Raton, FL: CRC Press; 2014.
53. Popoff M, Gleisberg W, editors. Cell Stimulation Research.
Berlin: 1924-1930.
54. Ayengar AR, Glubrecht H, Fendrik I, Bhattacharya S, editors.
Stimulation Newsletter. Germany: 1970-1976.
55. Luckey TD. Hormesis with Ionizing Radiation. Boca Raton, FL:
CRC Press, Inc.; 1980.
56. Luckey TD. Radiation Hormesis. Boca Raton, FL: CRC Press, Inc.;
1991.
57. Stebbing AR. Hormesis – Stimulation of colony growth in
campanularia‑exuosa (hydrozoa) by copper, cadmium and other
toxicants. Aquat Toxicol 1981;1:227-38.
58. Stebbing AR. The kinetics of growth-control in a colonial hydroid.
J Mar Biol Assoc UK 1981;61:35-63.
59. Stebbing AR. Hormesis – the stimulation of growth by low levels
of inhibitors. Sci Total Environ 1982;22:213-34.
60. Calabrese EJ, editor. Biological Effects of Low Level Exposures
to Chemicals and Radiation. Chelsea: Lewis Publishers, Inc.;
1992.
61. Calabrese EJ, editor. Biological Effects of Low Level Exposures
Dose-Response Relationships. Boca Raton: Lewis Publisher/CRC
Press, Inc.; 1994.
62. Calabrese EJ. Toxicological defense mechanisms and the
shape of dose-response relationships. Environ Health Perspect
1998;106 Suppl 1:276-394.
63. Calabrese EJ. Hormetic dose-response relationships in
immunology: Occurrence, quantitative features of the dose
response, mechanistic foundations, and clinical implications. Crit
Rev Toxicol 2005;35:89-295.
64. Calabrese EJ. Cancer biology and hormesis: Human tumor cell
lines commonly display hormetic (biphasic) dose responses. Crit
Rev Toxicol 2005;35:463-582.
65. Calabrese EJ. Adrenergic receptors: Biphasic dose responses. Crit
Rev Toxicol 2001;31:523-38.
66. Calabrese EJ. Prostaglandins: Biphasic dose responses. Crit Rev
Toxicol 2001;31:475-87.
67. Calabrese EJ. Adenosine: Biphasic dose responses. Crit Rev
Toxicol 2001;31:539-51.
68. Calabrese EJ. Nitric oxide: Biphasic dose responses. Crit Rev
Toxicol 2001;31:489-501.
69. Calabrese EJ. 5-Hydroxytryptamine (serotonin): Biphasic dose
responses. Crit Rev Toxicol 2001;31:553-61.
70. Calabrese EJ. Opiates: Biphasic dose responses. Crit Rev Toxicol
2001;31:585-604.
71. Calabrese EJ. Dopamine: Biphasic dose responses. Crit Rev Toxicol
2001;31:563-83.
72. Calabrese EJ. Estrogen and related compounds: Biphasic dose
responses. Crit Rev Toxicol 2001;31:503-15.
73. Calabrese EJ. Androgens: Biphasic dose responses. Crit Rev
Toxicol 2001;31:517-22.
74. Calabrese EJ, Blain R. Metals and hormesis. J Environ Monit
2004;6:14N-9N.
75. Calabrese EJ. Apoptosis: Biphasic dose responses. Crit Rev Toxicol
2001;31:607-13.
76. Calabrese EJ, Baldwin LA. The frequency of U-shaped dose
responses in the toxicological literature. Toxicol Sci 2001;62:330-8.
77. Calabrese EJ, Baldwin LA. The hormetic dose-response model is
more common than the threshold model in toxicology. Toxicol
Sci 2003;71:246-50.
78. Calabrese EJ, Staudenmayer JW, Stanek EJ 3rd, Hoffmann GR.
Hormesis outperforms threshold model in National Cancer
Institute antitumor drug screening database. Toxicol Sci
2006;94:368-78.
79. Calabrese EJ, Stanek EJ 3rd, Nascarella MA, Hoffmann GR.
Hormesis predicts low-dose responses better than threshold
models. Int J Toxicol 2008;27:369-78.
80. Calabrese EJ, Stanek EJ 3rd, Nascarella MA. Evidence for
hormesis in mutagenicity dose-response relationships. Mutat Res
2011;726:91-7.
81. Calabrese EJ. Evidence that hormesis represents an
“overcompensation” response to a disruption in homeostasis.
Ecotoxicol Environ Saf 1999;42:135-7.
82. Calabrese EJ. Overcompensation stimulation: A mechanism for
hormetic effects. Crit Rev Toxicol 2001;31:425-70.
83. Shook JR, Giordano J. Neuroethics beyond normal. Performance
enablement and self-transformative technologies. Camb Q.
Healthc Ethics 2016;25:121-40.
84. Gini A, Rossi J, Giordano J. Considering enhancement and
treatment: On the need to regard contingency and develop
dialectic evaluation. Am J Bioeth Neurosci 2010;1:25-7.
85. Shook JR, Galvagni L, Giordano J. Cognitive enhancement kept
within contexts: Neuroethics and informed public policy. Front
Syst Neurosci 2014;8:228.
86. Giordano J, Shook JR. Minding brain science in medicine: On the
need for neuroethical engagement for guidance of neuroscience
in clinical contexts. Ethics Biol Eng Med 2015;6:37-42.
87. Zhang C, Chen S, Bao J, Zhang Y, Huang B, Jia X, et al. Low doses
of camptothecin induced hormetic and neuroprotective effects in
PC12 cells. Dose Response 2015;13:1-7.
88. Gidday JM. Extending injury- and disease-resistant CNS
phenotypes by repetitive epigenetic conditioning. Front Neurol
2015;6:42.
89. Atif F, Sayeed I, Ishrat T, Stein DG. Progesterone with Vitamin D
affords better neuroprotection against excitotoxicity in cultured
cortical neurons than progesterone alone. Mol Med 2009;15:328-36.
90. Bradley E, Zhao X, Wang R, Brann D, Bieberich E, Wang G. Low
dose Hsp90 inhibitor 17AAG protects neural progenitor cells from
ischemia induced death. J Cell Commun Signal 2014;8:353-62.
Calabrese, et al.: Hormesis and neuroprotection
Brain Circulation - Volume 3, Issue 1, January-March 2017 13
91. Correia Sc, Santos Rx, Cardoso Sm, Santos Ms, Oliveira Cr, Moreira
Pi. Cyanide Preconditioning Protects Brain Endothelial And Nt2
Neuron-Like Cells Against Glucotoxicity: Role Of Mitochondrial
Reactive Oxygen Species And Hif-1A. Neurobiol Dis 2012;45:206-18.
92. Crawley JN, Blumstein LK, Baldino F Jr. Anxiolytic-like properties
of fominoben. Eur J Pharmacol 1984;97:277-81.
93. El Ayadi A, Zigmond MJ. Low concentrations of methamphetamine
can protect dopaminergic cells against a larger oxidative stress
injury: Mechanistic study. PLoS One 2011;6:e24722.
94. Galeotti N, Stefano GB, Guarna M, Bianchi E, Ghelardini C. Signaling
pathway of morphine induced acute thermal hyperalgesia in mice.
Pain 2006;123:294-305.
95. Honar H, Riazi K, Homayoun H, Sadeghipour H, Rashidi N,
Ebrahimkhani MR, et al. Ultra-low dose naltrexone potentiates
the anticonvulsant effect of low dose morphine on clonic seizures.
Neuroscience 2004;129:733-42.
96. Lauretti GR, Ahmad I, Pleuvry BJ. The activity of opioid analgesics
in seizure models utilizing N-methyl-DL-aspartic acid, kainic
acid, bicuculline and pentylenetetrazole. Neuropharmacology
1994;33:155-60.
97. Leung WC, Zheng H, Huen M, Law SL, Xue H. Anxiolytic-like
action of orally administered dl-tetrahydropalmatine in elevated
plus-maze. Prog Neuropsychopharmacol Biol Psychiatry
2003;27:775-9.
98. Melchior CL, Ritzmann RF. Dehydroepiandrosterone is an
anxiolytic in mice on the plus maze. Pharmacol Biochem Behav
1994;47:437-41.
99. Meng JL, Mei WY, Dong YF, Wang JH, Zhao CM, Lan AP,
et al. Heat shock protein 90 mediates cytoprotection by H2S
against chemical hypoxia-induced injury in PC12 cells. Clin Exp
Pharmacol Physiol 2011;38:42-9.
100. Gundimeda U, McNeill TH, Elhiani AA, Schiffman JE, Hinton DR,
Gopalakrishna R. Green tea polyphenols precondition against cell
death induced by oxygen-glucose deprivation via stimulation
of laminin receptor, generation of reactive oxygen species, and
activation of protein kinase Ce. J Biol Chem 2012;287:34694-708.
101. Qi H, Han Y, Rong J. Potential roles of PI3K/Akt and Nrf2-Keap1
pathways in regulating hormesis of Z-ligustilide in PC12 cells
against oxygen and glucose deprivation. Neuropharmacology
2012;62:1659-70.
102. Moriguchi T, Matsuura H, Itakura Y, Katsuki H, Saito H,
Nishiyama N. Allixin, a phytoalexin produced by garlic, and
its analogues as novel exogenous substances with neurotrophic
activity. Life Sci 1997;61:1413-20.
103. Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, et al.
Cannabinoids and neuroprotection in global and focal cerebral
ischemia and in neuronal cultures. J Neurosci 1999;19:2987-95.
104. O’Neill K, Chen S, Brinton RD. Impact of the selective estrogen
receptor modulator, raloxifene, on neuronal survival and
outgrowth following toxic insults associated with aging and
Alzheimer’s disease. Exp Neurol 2004;185:63-80.
105. Paalzow GH, Paalzow LK. Promethazine both facilitates and
inhibits nociception in rats: Effect of the testing procedure.
Psychopharmacology (Berl) 1985;85:31-6.
106. Rau TF, Kothiwai A, Zhang L, Ulatowski S, Jacobson S,
Brooks DM, et al. Low dose methamphetamine mediates
neuroprotection through a P13K-Akt pathway.
Neuropharmacology 2011;61:677-86.
107. Schafberg H, Nowak G, Kaufmann R. Thrombin has a bimodal
effect on glioma cell growth. Br J Cancer 1997;76:1592-5.
108. Sharma RK, Zhou Q, Netland PA. Effect of oxidative
preconditioning on neural progenitor cells. Brain Res
2008;1243:19-26.
109. Spinnewyn B, Cornet S, Auguet M, Chabrier PE. Synergistic
protective effects of antioxidant and nitric oxide synthase
inhibitor in transient focal ischemia. J Cereb Blood Flow Metab
1999;19:139-43.
110. Wang JM, Johnston PB, Ball BG, Brinton RD. The neurosteroid
allopregnanolone promotes proliferation of rodent and human
neural progenitor cells and regulates cell-cycle gene and protein
expression. J Neurosci 2005;25:4706-18.
111. Wei H, Ming QZ, Li Z, Qian C, Fang D, Ho YW, et al. Ginkgolides
mimic the effects of hypoxid preconditioning to protect C6 cells
against ischemic injury by up-regulation of hypoxia-inducible
factor-1 alpha and erythropoietin. Int J Biochem Cell Biol
2008;40:651-62.
112. Wu XM, Qian ZM, Zhu L, Du F, Yung WH, Gong Q, et al.
Neuroprotective effect of ligustilide against ischaemia-reperfusion
injury via up-regulation of erythropoietin and down-regulation
of RTP801. Br J Pharm 2011;164:332-43.
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