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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 5, Number 2, June 2007
Contents
The Cannabinoid CB2 Receptor as a Target for Inflammation
Dependent Neurodegeneration Pp. 73-80
J.C. Ashton and M. Glass
[Abstract]
Neuropharmacology of the Endocannabinoid Signaling
System Molecular Mechanisms, Biological Actions and Synaptic
Plasticity Pp. 81-97
B.S. Basavarajappa
[Abstract]
Parkinson’s Disease: Genetics and Beyond
Pp. 99-113
N.N. Inamdar, D.K. Arulmozhi, A. Tandon and S.L. Bodhankar
[Abstract]
Cell and Gene Therapies for Refractory Epilepsy
Pp. 115-125
D. Boison
[Abstract]
Current Experimental Therapy for Alzheimer’s
Disease Pp. 127-134
S. Chen, X.-J. Zhang, L. Li and W.-D. Le
[Abstract]
The Neurobiological Bases for Development of Pharmacological
Treatments of Aggressive Disorders Pp. 135-147
A. Siegel, S. Bhatt, R. Bhatt and S.S. Zalcman
[Abstract]
Abstracts
[Back to top]
The Cannabinoid CB2 Receptor as a Target for Inflammation
Dependent Neurodegeneration
J.C. Ashton and M. Glass
Endocannabinoids are released following brain injury and may
protect against excitotoxic damage during the acute stage
of injury. Brain injury also activates microglia in a secondary
inflammatory phase of more widespread damage. Most drugs targeting
the acute stage are not effective if administered more than
6 hours after injury. Therefore, drugs targeting microglia
later in the neurodegenerative cascade are desirable. We have
found that cannabinoid CB2 receptors are upregulated during
the activation of microglia following brain injury. Specifically,
CB2-positive cells appear in the rat brain following both
hypoxia-ischemia (HI) and middle cerebral artery occlusion
(MCAO). This may regulate post-injury microglial activation
and inflammatory functions. In this paper we review in
vivo and in vitro studies of CB2 receptors in
microglia, including our results on CB2 expression post-injury.
Taken together, studies show that CB2 is up-regulated during
a process in which microglia become primed to proliferate,
and then become fully reactive. In addition, CB2 activation
appears to prevent or decrease microglial activation. In a
rodent model of Alzheimer's disease microglial activation
was completely prevented by administration of a selective
CB2 agonist. The presence of CB2 receptors in microglia in
the human Alzheimer’s diseased brain suggests that CB2
may provide a novel target for a range of neuropathologies.
We conclude that the administration of CB2 agonists and antagonists
may differentially alter microglia-dependent neuroinflammation.
CB2 specific compounds have considerable therapeutic appeal
over CB1 compounds, as the exclusive expression of CB2 on
immune cells within the brain provides a highly specialised
target, without the psychoactivity that plagues CB1 directed
therapies.
[Back to top]
Neuropharmacology of the Endocannabinoid Signaling
System Molecular Mechanisms, Biological Actions and Synaptic
Plasticity
B.S. Basavarajappa
The endocannabinoid signaling system is composed of the cannabinoid
receptors; their endogenous ligands, the endocannabinoids;
the enzymes that produce and inactivate the endocannabinoids;
and the endocannabinoid transporters. The endocannabinoids
are a new family of lipidic signal mediators, which includes
amides, esters, and ethers of long-chain polyunsaturated fatty
acids. Endocannabinoids signal through the same cell surface
receptors that are targeted by Δ9-tetrahydrocannabinol
(Δ9-THC), the active
principles of cannabis sativa preparations like hashish
and marijuana. The biosynthetic pathways for the synthesis
and release of endocannabinoids are still rather uncertain.
Unlike neurotransmitter molecules that are typically held
in vesicles before synaptic release, endocannabinoids are
synthesized on demand within the plasma membrane. Once released,
they travel in a retrograde direction and transiently suppress
presynaptic neurotransmitter release through activation of
cannabinoid receptors. The endocannabinoid signaling system
is being found to be involved in an increasing number of pathological
conditions. In the brain, endocannabinoid signaling is mostly
inhibitory and suggests a role for cannabinoids as therapeutic
agents in central nervous system (CNS) disease. Their ability
to modulate synaptic efficacy has a wide range of functional
consequences and provides unique therapeutic possibilities.
The present review is focused on new information regarding
the endocannabinoid signaling system in the brain. First,
the structure, anatomical distribution, and signal transduction
mechanisms of cannabinoid receptors are described. Second,
the synthetic pathways of endocannabinoids are discussed,
along with the putative mechanisms of their release, uptake,
and degradation. Finally, the role of the endocannabinoid
signaling system in the CNS and its potential as a therapeutic
target in various CNS disease conditions, including alcoholism,
are discussed.
[Back to top]
Parkinson’s Disease: Genetics and Beyond
N.N. Inamdar, D.K. Arulmozhi, A. Tandon and S.L. Bodhankar
Parkinson’s disease (PD) is characterized clinically
by resting tremor, rigidity, bradykinesia and postural instability
due to progressive and selective loss of dopamine neurons
in the ventral substantia nigra, with the presence of ubiquitinated
protein deposits called Lewy bodies in the neurons. The pathoetiology
of cell death in PD is incompletely understood and evidence
implicates impaired mitochondrial complex I function, altered
intracellular redox state, activation of proapoptotic factors
and dysfunction of ubiquitin-proteasome pathway. Now it is
believed that genetic aberration, an environmental toxin or
combination of both leads to a cascade of events culminating
in the destruction of myelinated brainstem catecholaminergic
neurons. Also the role of production of significant levels
of abnormal proteins, which may misfold, aggregate and interfere
with intracellular processes causing cytotoxicity has recently
been hypothesized. In this article, the diverse pieces of
evidence that have linked the various factors responsible
for the pathophysiology of PD are reviewed with special emphasis
to various candidate genes and proteins. Furthermore, the
present therapeutic strategies and futuristic approaches for
the pharmacotherapy of PD are critically discussed.
[Back to top]
Cell and Gene Therapies for Refractory Epilepsy
D. Boison
Despite recent advances in the development of antiepileptic
drugs, refractory epilepsy remains a major clinical problem
affecting up to 35% of patients with partial epilepsy. Currently,
there are few therapies that affect the underlying disease
process. Therefore, novel therapeutic concepts are urgently
needed. The recent development of experimental cell and gene
therapies may offer several advantages compared to conventional
systemic pharmacotherapy: (i) Specificity to underlying
pathogenetic mechanisms by rational design; (ii)
specificity to epileptogenic networks by focal delivery; and
(iii) avoidance of side effects. A number of naturally
occurring brain sub-stances, such as GABA, adenosine, and
the neuropeptides galanin and neuropeptide Y, may function
as endogenous anticonvulsants and, in addition, may interact
with the process of epileptogenesis. Unfortunately, the systemic
application of these compounds is compromised by limited bioavailability,
poor penetration of the blood-brain barrier, or the widespread
systemic distribution of their respective receptors. Therefore,
in recent years a new field of cell and gene-based neuropharmacology
has emerged, aimed at either delivering endogenous anticonvulsant
compounds by focal intracerebral transplantation of bioengineered
cells (ex vivo gene therapy), or by inducing epileptogenic
brain areas to produce these compounds in situ (in
vivo gene therapy). In this review, recent efforts to
develop GABA-, adenosine-, galanin-, and neuropeptide Y- based
cell and gene therapies are discussed. The neurochemical rationales
for using these compounds are discussed, the advantages of
focal applications are highlighted and preclinical cell transplantation
and gene therapy studies are critically evaluated. Although
many promising data have been generated recently, potential
problems, such as long-term therapeutic efficacy, long-term
safety, and efficacy in clinically relevant animal models,
need to be addressed before clinical applications can be contemplated.
[Back to top]
Current Experimental Therapy for Alzheimer’s
Disease
S. Chen, X.-J. Zhang, L. Li and W.-D. Le
In the past decade, enormous efforts have been devoted to
understand the genetics and molecular pathogenesis of Alzheimer’s
disease (AD), which has been transferred into extensive experimental
approaches aimed at reversing disease progression. The trend
in future AD therapy has been shifted from traditional anti-acetylcholinesterase
treatment to multiple mechanisms-based therapy targeting amyloid
plaques formation and amyloid peptides (Aβ)-mediated
cytotoxicity, and neurofibrillary tangles generation. This
review will cover current experimental studies with the focus
on secretases-based drug development, immunotherapy, and anti-neurofibrillary
tangles intervention. The outcome of these on-going studies
may provide high hope that AD can be cured in the future.
[Back to top]
The Neurobiological Bases for Development of Pharmacological
Treatments of Aggressive Disorders
A. Siegel, S. Bhatt, R. Bhatt and S.S. Zalcman
Violence and aggression are major causes of death and injury,
thus constituting primary public health problems throughout
much of the world costing billions of dollars to society.
The present review relates our understanding of the neurobiology
of aggression and rage to pharmacological treatment strategies
that have been utilized and those which may be applied in
the future. Knowledge of the neural mechanisms governing aggression
and rage is derived from studies in cat and rodents. The primary
brain structures involved in the expression of rage behavior
include the hypothalamus and midbrain periaqueductal gray.
Limbic structures, which include amygdala, hippocampal formation,
septal area, prefrontal cortex and anterior cingulate gyrus
serve important modulating functions. Excitatory neurotransmitters
that potentiate rage behavior include excitatory amino acids,
substance P, catecholamines, cholecystokinin, vasopressin,
and serotonin that act through 5-HT2
receptors. Inhibitory neurotransmitters include GABA, enkephalins,
and serotonin that act through 5-HT1
receptors. Recent studies have demonstrated that brain cytokines,
including IL-1β
and IL-2, powerfully modulate rage behavior. IL-1β
exerts its actions by acting through 5-HT2
receptors, while IL-2 acts through GABAA
or NK1 receptors. Pharmacological
treatment strategies utilized for control of violent behavior
have met with varying degrees of success. The most common
approach has been to apply serotonergic compounds. Others
included the application of antipsychotic, GABAergic (anti-epileptic)
and dopaminergic drugs. Present and futures studies on the
neurobiology of aggression may provide the basis for new and
novel treatment strategies for the control of aggression and
violence as well as the continuation of existing pharmacological
approaches.
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