A requirement for astrocyte IP3R2 signaling for whisker experience-dependent depression and homeostatic upregulation in the mouse barrel cortex
Authors : John B. Butcher1,2‡, Robert E. Sims2†‡, Neville M. Ngum2, Amjad H. Bazzari2, Stuart I. Jenkins3, Marianne King2, Eric J. Hill2, David A. Nagel4, Kevin Fox5, H. Rheinallt Parri2*§ and Stanislaw Glazewski1*§
Abstract : Changes to sensory experience result in plasticity of synapses in the cortex. This
experience-dependent plasticity (EDP) is a fundamental property of the brain. Yet, while much is
known about neuronal roles in EDP, very little is known about the role of astrocytes. To address this
issue, we used the well-described mouse whiskers-to-barrel cortex system, which expresses a number
of forms of EDP. We found that all-whisker deprivation induced characteristic experience-dependent
Hebbian depression (EDHD) followed by homeostatic upregulation in L2/3 barrel cortex of wild type
mice. However, these changes were not seen in mutant animals (IP3R2–/–) that lack the astrocyteexpressed IP3 receptor subtype. A separate paradigm, the single-whisker experience, induced
potentiation of whisker-induced response in both wild-type (WT) mice and IP3R2–/– mice. Recordings
in ex vivo barrel cortex slices reflected the in vivo results so that long-term depression (LTD) could not
be elicited in slices from IP3R2–/– mice, but long-term potentiation (LTP) could. Interestingly, 1 Hz
stimulation inducing LTD in WT paradoxically resulted in NMDAR-dependent LTP in slices from
IP3R2–/– animals. The LTD to LTP switch was mimicked by acute buffering astrocytic [Ca2+]i in WT
slices. Both WT LTD and IP3R2–/– 1 Hz LTP were mediated by non-ionotropic NMDAR signaling, but
only WT LTD was P38 MAPK dependent, indicating an underlying mechanistic switch. These results
demonstrate a critical role for astrocytic [Ca2+]i in several EDP mechanisms in neocortex.
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BDNF Therapeutic Mechanisms in Neuropsychiatric Disorders
Authors : Amjad H. Bazzari 1,Firas H. Bazzari 2
Abstract : Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the adult
brain and functions as both a primary neurotrophic signal and a neuromodulator. It serves essential
roles in neuronal development, maintenance, transmission, and plasticity, thereby influencing aging,
cognition, and behavior. Accumulating evidence associates reduced central and peripheral BDNF
levels with various neuropsychiatric disorders, supporting its potential utilization as a biomarker of
central pathologies. Subsequently, extensive research has been conducted to evaluate restoring, or
otherwise augmenting, BDNF transmission as a potential therapeutic approach. Promising results
were indeed observed for genetic BDNF upregulation or exogenous administration using a multitude
of murine models of neurological and psychiatric diseases. However, varying mechanisms have been
proposed to underlie the observed therapeutic effects, and many findings indicate the engagement of
disease-specific and other non-specific mechanisms. This is because BDNF essentially affects all
aspects of neuronal cellular function through tropomyosin receptor kinase B (TrkB) receptor signaling,
the disruptions of which vary between brain regions across different pathologies leading to diversified
consequences on cognition and behavior. Herein, we review the neurophysiology of BDNF
transmission and signaling and classify the converging and diverging molecular mechanisms
underlying its therapeutic potentials in neuropsychiatric disorders. These include neuroprotection,
synaptic maintenance, immunomodulation, plasticity facilitation, secondary neuromodulation, and
preservation of neurovascular unit integrity and cellular viability. Lastly, we discuss several findings
suggesting BDNF as a common mediator of the therapeutic actions of centrally acting pharmacological
agents used in the treatment of neurological and psychiatric illness.
Keywords : brain-derived neurotrophic factor; TrkB signaling; neuroprotection; synaptic plasticity; neuromodulation; neurodegeneration; neuroinflammation; oxidative stress
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Advances in targeting central sensitization and brain plasticity in chronic pain
Authors : Amjad H. Bazzari & Firas H. Bazzari
Abstract : Maladaptation in sensory neural plasticity of nociceptive pathways is associated with various types of chronic pain through central sensitization and remodeling of brain connectivity. Within this context, extensive research has been conducted to evaluate the mechanisms and efficacy of certain non-pharmacological pain treatment modalities. These include neurostimulation, virtual reality, cognitive therapy and rehabilitation. Here, we summarize the involved mechanisms and review novel findings in relation to nociceptive desensitization and modulation of plasticity for the management of intractable chronic pain and prevention of acute-to-chronic pain transition.
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Lucid dreaming and associated sleep and dream factors among university students in West
Bank Palestine
Authors : Firas H. Bazzari (Author)
Amjad H. Bazzari (Author)
Abstract : Lucid dreaming is a phenomenon in which the dreamer is aware that he/she is dreaming while the dream is still going on. Many studies investigated the prevalence of lucid dreaming in various populations; however, no study has been conducted in the Arab Middle East region. As age and cultural differences in attitudes towards dreams may influence lucid dreaming, we aimed to investigate lucid dreaming and associated sleep characteristics among university students in West Bank Palestine. This cross-sectional study was conducted through an online questionnaire and a total of 390 students participated. The results revealed a prevalence of 71% and frequency of 0.77 (SD=1.85) lucid dreams/month. The awareness level of lucid dreaming was 38.5% and significantly associated with lucid dreaming incidence. Participant demographics and certain sleep factors such as sleep time, latency, duration and perceived quality did not influence lucid dreaming. However, nocturnal awakening significantly associated with the occurrence of lucid dreams. Dream characteristics including dream frequency, dream recall, day-dreaming and perceived meaningfulness of dreams were all associated with lucid dreaming and positively correlated with its frequency. The results show comparable lucid dreaming patterns to other populations and indicate its dependence on many dream characteristics.
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Neuromodulators and Long-Term Synaptic Plasticity in Learning and Memory: A Steered-Glutamatergic Perspective
Authors : Amjad H. Bazzari * and H. Rheinallt Parri
Abstract : The molecular pathways underlying the induction and maintenance of long-term synaptic
plasticity have been extensively investigated revealing various mechanisms by which neurons control
their synaptic strength. The dynamic nature of neuronal connections combined with plasticity-mediated
long-lasting structural and functional alterations provide valuable insights into neuronal encoding
processes as molecular substrates of not only learning and memory but potentially other sensory,
motor and behavioural functions that reflect previous experience. However, one key element receiving
little attention in the study of synaptic plasticity is the role of neuromodulators, which are known to
orchestrate neuronal activity on brain-wide, network and synaptic scales. We aim to review current
evidence on the mechanisms by which certain modulators, namely dopamine, acetylcholine,
noradrenaline and serotonin, control synaptic plasticity induction through corresponding metabotropic
receptors in a pathway-specific manner. Lastly, we propose that neuromodulators control plasticity
outcomes through steering glutamatergic transmission, thereby gating its induction and maintenance.
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Orofacial neuropathic pain: a pharmacological approach
Authors : F.H. Bazzari, A.H. Bazzari
Abstract : Orofacial neuropathic pain is a medical condition that arises due to somatosensory nervous
system injury or disease in the orofacial region. Multiple types of orofacial neuropathic pain have been
identified, such as nonodontogenic neuropathic orofacial pain, trigeminal neuralgia, postherpetic
neuralgia, atypical odontalgia and glossopharyngeal neuralgia. To date, pharmacological intervention
is considered the cornerstone in the management of neuropathic pain. Drugs from different classes
including anticonvulsants, antidepressants, opioids, nonsteroidal anti-inflammatory drugs and others
are commonly used in the treatment of neuropathy. Nevertheless, the majority of these drugs are yet
to be approved by the food and drug administration for neuropathy. This review will explore recent
clinical findings and pieces of evidence regarding medical agents used in the management of orofacial
neuropathic pain and will discuss their efficacy and mode of action, at the same time highlighting a
number of promising therapeutic options.
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edicinal plants for Alzheimer’s disease: An updated review
Authors : Amjad Hasan Bazzari and Firas Hasan Bazzari
Abstract : Alzheimer’s disease is the major cause of dementia worldwide. The number of patients
suffering from dementia continue to rise reaching pandemic levels. Alzheimer’s disease is highly
debilitating; starting from memory complains leading ultimately to complete dependence and inability
to perform daily living tasks. Late initiation of Alzheimer’s disease medications is argued to reduce
their efficacy. The current treatment options provide symptomatic improvement without hindering the
disease progression. The lack of disease-modifying drugs necessitates the development of newer
therapeutic agents and different target-based strategies due to the complexity of underlying
pathologies. Various plants and herbal preparations have been traditionally used for their memory and
cognitive enhancing abilities; many of which were extensively studied in the last few years for
therapeutic potential in Alzheimer’s disease. This review will focus on recent research finding
regarding the efficacy of various plants according to their; cognitive enhancing, neuroprotective,
antioxidant, and anti-inflammatory properties in Alzheimer’s disease.
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Drug-Induced Delirium: A Mini Review
Authors : Firas Hasan Bazzari
, Amjad Hasan Bazzari
Abstract : Delirium is a neuropsychiatric disorder that has detrimental futuristic complications, ranging
from long-term cognitive impairment to death within several months, especially in the elderly and
critically ill patients. One of the key elements in delirium management is to assess, identify and control
any associated risk factors. Elevated risk and incidence of delirium have been reported with the use
of a number of drugs from various pharmacological classes. Different medical agents indicated for
cardiovascular conditions, central nervous system (CNS) disorders, anesthesia, cancer
chemotherapy, and other medical conditions, have been reported to precipitate delirium episodes.
Therefore, cautious assessment and continuous monitoring of patients’ medical profiles may
significantly reduce the risk of delirium. This mini review aims to explore the recently published
scientific evidence on drug-induced delirium; in addition, attempting to find reasonable relations
between the drugs’ mode of action and delirium pathogenesis. Ultimately, providing medical
experts with an update and a brief overview for the uprising scientists in the field.
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Promising Therapeutic Agents: Delta Opioid Receptor Agonists
Authors : A. H. Bazzari, F. H. Bazzari
Abstract : Adequate characterization of the endogenous opioid system’s peptides and receptors;
in addition to, the development of highly selective ligands, have improved research approaches and
understanding the roles of this system. Delta-Opioid Receptor (DOR) was found to exhibit distinctive
pharmacological profile and tissue distribution compared to other opioid receptors. Hence, DOR has
been extensively investigated in the last decade as a potential target in the treatment of various
disorders. Research findings indicate high potential of DOR agonists in the modulation of brain as well
as cardiovascular system functions. DOR activation was found to display cytoprotective effects against
ischemia/reperfusion injury in neurons and cardiomyocytes. DOR affects cellular functions on the level
of gene expression, ion channels, enzymatic activity and membrane-receptors functions through
multiple signaling pathways and second messenger systems. Moreover, DOR has been implicated in
mood disorders; in vivo administration of DOR agonists and enkephalinase inhibitors had significant
anxiolytic and antidepressant effects. More recent research findings have shown consistent and
statistically significant results on DOR activation beneficial effects in cardiac conditioning, neural
ischemia protection, anxiety and depression management. Further advances in research would
potentially reveal the exact molecular mechanisms underlying DOR functions in relation to receptor
subtypes and signaling pathways.
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