Brain Injuries Clinical Trial
Official title:
Promotion of Synaptic Plasticity With D-Aspartate to Favour Recovery Form Cerebral Damage
An important mechanism responsible for clinical recovery after neurological damage of
different types is synaptic plasticity. Nervous tissue can enhance or de-energize
inter-neuronal transmission at synaptic level in a lasting way. By increasing the efficiency
of synaptic transmission, through long-term potentiation (LTP), it is possible to compensate
for the loss of synaptic pulses on survived neurons due to brain damage and to restore their
function.
At synaptic level, LTP is mainly regulated by NMDA receptors. In animal models induction of
plasticity in surviving neurons through the stimulation of NMDA receptors has been shown to
limit the clinical manifestations of neuronal damage. Endogenous NMDA is synthesized by
methylation of D-aspartate (Asp) by D-aspartatoartate methyltransferase . Moreover, Asp acts
as a neurotransmitter capable of activating the NMDA receptor, since its biosynthesis,
degradation, absorption and release occurs in the pre-synaptic neuron, and its release
determines a response in Post-synaptic neurons. The expression of Asp in the SNC is very
abundant during the embryonic period and in early years, whereas it is significantly reduced
in adulthood.
Consistent with Asp ability of activating the NMDA receptor, recent studies have shown that
oral administration of Asp increases LTP induction in mice. Preliminary studies by our group
also showed an increase in LTP amplitude in subjects suffering from progressive forms of
Multiple Sclerosis after 2 weeks of daily per os intake of 2660mg Asp.
It is also well known that the therapeutic exercise that characterizes a rehabilitative
treatment is able to induce various benefits to the physical-functional and the
cognitive-emotional spheres. In this regard, it has been extensively demonstrated how
repeatedly performing a motor task can increase cortical excitability through the induction
of LTP mechanisms.
Hypothesis Pharmacologically promoting the induction of cortical LTP by the intake of Asp in
subjects with various types of brain damage (eg Multiple Sclerosis, Parkinson's Disease,
Dementia) may favor the therapeutic effects of rehabilitative treatment.
Specific Objectives Evaluate the effects of Asp in improving the outcome of rehabilitative
treatment resulting from brain damage of different origin.
An important mechanism responsible for clinical recovery after neurological damage of
different types is synaptic plasticity. Nervous tissue can enhance or de-energize
inter-neuronal transmission at synaptic level in a lasting way. By increasing the efficiency
of synaptic transmission, through long-term potentiation (LTP), it is possible to compensate
for the loss of synaptic pulses on survived neurons due to brain damage and to restore their
function.
At synaptic level, LTP is mainly regulated by NMDA receptors. In animal models induction of
plasticity in surviving neurons through the stimulation of NMDA receptors has been shown to
limit the clinical manifestations of neuronal damage. Endogenous NMDA is synthesized by
methylation of D-aspartate (Asp) by D-aspartatoartate methyltransferase . Moreover, Asp acts
as a neurotransmitter capable of activating the NMDA receptor, since its biosynthesis,
degradation, absorption and release occurs in the pre-synaptic neuron, and its release
determines a response in Post-synaptic neurons. The expression of Asp in the SNC is very
abundant during the embryonic period and in early years, whereas it is significantly reduced
in adulthood.
Consistent with Asp ability of activating the NMDA receptor, recent studies have shown that
oral administration of Asp increases LTP induction in mice. Preliminary studies by our group
also showed an increase in LTP amplitude in subjects suffering from progressive forms of
Multiple Sclerosis after 2 weeks of daily per os intake of 2660mg Asp.
It is also well known that the therapeutic exercise that characterizes a rehabilitative
treatment is able to induce various benefits to the physical-functional and the
cognitive-emotional spheres. In this regard, it has been extensively demonstrated how
repeatedly performing a motor task can increase cortical excitability through the induction
of LTP mechanisms.
Hypothesis Pharmacologically promoting the induction of cortical LTP by the intake of Asp in
subjects with various types of brain damage (eg Multiple Sclerosis, Parkinson's Disease,
Dementia) may favor the therapeutic effects of rehabilitative treatment.
Specific Objectives A double-blind study to evaluate the effects of D-aspartate in improving
the outcome of rehabilitative treatment resulting from brain damage of different origin (eg
Multiple Sclerosis, Parkinson's Disease, Dementia). This will be made possible thanks to the
specific skills of a multidisciplinary team of neurologists and physiatrists, healthcare
professionals such as physiotherapists, occupational therapists, psychologists, speech
therapists and the support of a biomedical engineer. These professional figures are already
available at the UCK Neurosurgery of the IRCCS Neuromed directed by the proposer and actively
collaborate to optimize the therapeutic exercise of patients with neurological damage.
Population of the study This study aims to provide preliminary data on interaction between
D-aspartate and therapeutic exercise in inducing LTP cortical phenomena. The sample estimate
was made by analogy after a literature analysis. In view of the quite high risk of drop out,
our intention is to recruit at least 100 subjects in a population of patients with cerebral
injury of various origin, coming to the neurology department of IRRCS Neuromed, Pozzilli.
Inclusion and exclusion criteria are as specified below.
Study design Double-blind prospective study, between randomized, placebo-controlled parallel
groups.
Recruited patients will be randomized to receive 2660 mg D-aspartate oral dosing once daily
or placebo, in addition to the conventional treatment provided by the relevant staff, for a
period of 6 weeks. Patients will also be undergoing a Therapeutic Exercise Program (ET). All
conventional therapies taken by patients will be recorded by the operators. Patients will be
evaluated at zero time before starting treatment (T-0W) after 6 weeks to evaluate the effects
at the end of treatment (T-6W) , and at 12 weeks (T-12W) to evaluate the maintenance of
long-term effects. Randomization will be balanced in accordance with age, sex and schooling.
The physiotherapy and/or speech therapy approach will differ among patients considering the
different types of brain damage and the different levels of disability, according to the
rehabilitation unit team for each case.
Expected results The present study aims to investigate whether the association between
pharmacological treatment with D-aspartate and therapeutic exercise may be more effective
than just therapeutic exercise in favor of synaptic plasticity and clinical recovery under
it, in patients with various forms of brain damage.
The expected result based on previous studies on mice (Errico, 2008, Errico, 2011) is that
D-aspartate, promoting neuronal plasticity and acting in synergy with therapeutic exercise,
strengthens the recovery of deficits in patients with various types of brain damage.
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