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is an essential process involving the ability to manage functions such as learning,
attention and memory – all of which are major components of intellectual
development (Albert et al. 2011). The
molecular mechanisms of Alzheimer’s disease (AD) and other dementias in
addition to traumatic brain injury (TBI), frequently result in cognitive deficits
with predominant signs of severe memory loss, poor judgment and difficulty
carrying out tasks (Albert et al.
2011). Cognitive impairment not only poses a significant threat on quality of
life, but it is also extremely costly with the average expenditure of $674
million in the United States during 2010 (Husain and
Mehta, 2011). As a consequence, the increasing need for pharmacological intervention
to enhance cognition has become a crucial focus
of therapeutic research in neurological disease and injury (Husain and Mehta, 2011).

Alzheimer’s Disease – Future Epidemic?

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AD is a neurodegenerative disease with characteristic
disturbances of higher cortical functions including memory and learning (Clegg
et al. 2001). AD is the most common form of
dementia mainly affecting elderly individuals over the age of 65, and as a
result of the ageing populations worldwide, there is a significant growing
socio-economic burden (Mangialasche et al. 2010). Despite there being
no definitive cure for AD, pharmacological research remains focused in
targeting the associated pathways and symptoms (Parnetti,
et al. 1997).


Current Treatment:
Cholinesterase Inhibitors (ChEIs)

Cholinergic pathways
within the brain hold a particular importance in cognitive functions, however
in patients with AD, evidence shows downregulation in cholinergic signalling
leading to cognitive decline (Mufson et
al. 2008). The most promising pharmacological treatment involves the use of
cholinesterase inhibitors which prevent
the hydrolysis of the neurotransmitter acetylcholine, and therefore maintain
cholinergic signalling within key cognition regions (Schneider et al. 1998). Since the introduction of
the first AChEI in 1997, most clinicians prescribe donepezil and rivastigmine
as the first line of treatment for patients with mild to moderate AD. Although
these drugs have slightly different pharmacological properties, the ultimate mechanism
of action is to block the enzyme acetylcholinesterase, in order to increase the
concentration of acetylcholine at cholinergic synapses, as shown in Figure 1 (Mufson et al.




Figure 1: A
schematic diagram representing the neurotransmission of acetylcholine in a
cholinergic synapse. Cholinesterase inhibitors prevent the enzyme
acetylcholinesterase from naturally hydrolysing acetylcholine and thereby
maximise the concentration and signalling.









Donepezil has been used for more than
a decade with an approved daily dose of 5-

10 mg/day. Adverse effects of
donepezil include gastrointestinal disturbances, nausea and fatigue whereas
contraindications involve bradycardia bronchospasm and seizures (Lee et al. 2015). On the other hand, rivastigmine
has been approved with a slightly higher daily dose of 6-12 mg/day, but unlike
donepezil, it inhibits butyrylcholinesterase as well as acetylcholinesterase (Camps and Munoz-Torrero, 2002). The associated adverse
effects are similar with common reports of nausea, vomiting and fatigue (Camps
and Munoz-Torrero, 2002).


Two studies have been undertaken to
compare the clinical efficacy of donepezil and rivastigmine (Hansen et al. 2008). The first was a two-year
double-blinded randomised trial comparing donepezil (5-10 mg/day) and rivastigmine
(3-12 mg/day) in 994 patients (Hansen et
al. 2008). Similar improvements in cognition were observed with both drugs,
although rivastigmine-treated patients also had a significant improvement in
function (Hansen et al. 2008). The
second study, was a 2-week open-label trial where donepezil (5–10 mg/day) and
rivastigmine (6–12 mg/day) were assessed in 111 patients, however, there was no
significant improvement in cognition (Hansen et al. 2008). Although both studies suggest that long-term
treatment with AChIEs has a larger influence in cognitive function, the
validity of conclusions cannot be determined due to differences in trial design
and that the first study was funded by rivastigmine manufacturers, and the
second study funded by donepezil manufacturers (Hansen et al. 2008).


Future Treatment: NDMA Antagonists

Whilst the degeneration of cholinergic neurones is considered
to be a pivotal cause of cognitive impairment in AD (Coyle et al. 1983), there are several other neurotransmitter systems that
are disrupted, including the excitatory amino acid glutamate and aspartate (Tsai et al. 1999).
A central mechanism in learning and memory is long-term potentiation (LTP),
which is mediated by glutamate via the N-methyl-d-aspartate (NMDA) receptors in
areas of the brain that are involved in memory and learning (Thomas et al. 2009).  The excess activation of
glutamatergic receptors is common in AD, and has been found to induce to an
excess accumulation of calcium, this is known as glutamate excitotoxicity and
contributes to cognitive defects (Sucher et
al. 1997). Therefore, this
pathway has been considered a suitable target for cognitive enhancement through
the use of NDMA receptor antagonists, which upon binding, prevent the influx of
calcium thus inhibit excitotoxicity (Thomas et
al. 2009).

Memantine is a non-competitive antagonist of
NMDA receptors which inhibits the destructive effect of glutamate signalling (Minkeviciene et al.
2008). Studies have demonstrated that this antagonist binds to human
cortical NMDA receptors with a Ki of approximately 0.5 mM, and inhibits
NMDA-evoked currents in rat hippocampal neurons with an IC50 of approximately 1
mM (Parsons et al. 1993, 1999, 2013).
In several controlled clinical trials, memantine
has demonstrated well tolerated effects and been beneficial in measures of
cognition (Parsons et al. 2013). Combination
therapy with memantine and an AChEI has been considered an effective approach
in the clinical setting and a promising advance in the treatment of cognitive
impairment in AD (Parsons et al.
2013). Preclinical data from animal studies, has shown how both drugs act via
different, but interconnected pathways, and their synergic activity may produce
greater affects than either drug alone (Parsons et al. 2013).

Traumatic Brain Injury

TBI affects up to 5.3 million individuals in the
United States, with 80% of sufferers reporting cognitive impairment (Titus et al. 2016).
Neurocognitive consequences of TBI include disturbances of attention, memory, and executive functioning (Arciniegas et al.
2002), and can be attributed to damage
vulnerable brain regions including the medial temporal regions, dorso-lateral
prefrontal cortex and sub-cortical white matter tracts (McAllister, 2011). Notably, in MRI
studies of TBI patients, a significant proportion of patients demonstrate
atrophy in the hippocampus – a crucial structure responsible for declarative
memory formation (Bigler et al. 1997). Following TBI,
calcium homeostasis is impaired and disrupts signalling pathways involving
protein kinases CaMKII and MAPK, which play important roles in the phosphorylation
of downstream effectors associated with the induction of  LTP and long-term depression (LTD) – two of
the major molecular mechanisms underlying learning and memory (Walker and Tesco, 2013). Current therapeutic options
available for cognitive defects in TBI include the CNS stimulant
methylphenidate, however in general, pharmacological intervention to improve or
reverse cognitive impairment in TBI is limited. Nevertheless, there is
current ongoing intensive research surrounding this subject (Titus et al. 2016).


Treatment: PDE4B Inhibition?

study conducted by Titus et al in
2016, showed that the selective PDE4B inhibitor, A33, has procognitive benefits
on adult male Sprague-Dawley rats who suffered parasagittal fluid-percussion
induced TBI, and therefore may be an effective intervention in humans. The
underlying molecular cascade resulting from this type of TBI involves cyclic
adenosine monophosphate (cAMP) and cAMP-response-element-bind protein (CREB)
activation, another pathway crucial in the function of memory and learning (Titus et al. 2016).
A decrease in cAMP is associated with an upregulation of the enzyme PDE4 which
degrades cAMP (Oliva et al. 2012).
Originally, it was found that the non-selective PDE inhibitor, rolipram, restored
cAMP levels and therefore increased CREB phosphorylation in injured rats, this
significantly improved LTP and learning after TBI (Titus et al. 2013). However, following
these promising results, the clinical development of rolipram was terminated
due to problematic pharmacokinetic characteristics such as a narrow therapeutic
window and severe emetic adverse effects (Titus et al. 2013).


the evaluation of rolipram trails, it was later hypothesised that a more
selective inhibitor specific to PDE4 may avoid undesirable adverse effects and
achieve clinical success (Titus et al.
2016). Recent drug discovery approaches have developed a PDE4B selective
inhibitor A33, which has a more specific affinity for PDE4B with an IC50 of 32
nM, is 49-fold more selective for PDE4B compared to PDE4D, and appears to not
inhibit any other PDE subtypes (Titus et
al. 2016). In comparison, rolipram had a lower affinity with an IC50 of 225
nM toward PDE4B and 288 nM toward PDE4D (Burgin et al. 2010). When A33
was administered to the rats, there was significant improvement of performances
in several cognitive tasks. The study ultimately concludes that the selective PDE4B
inhibitor A33 reduces learning and memory impairments and rescues expression of
hippocampal LTP after TBI (Titus et al.
2016) The results obtained theorise that A33 has the potential to be an
effective therapeutic approach in improving cognitive impairment in TBI and perhaps
various other neurological conditions, should it succeed in further
developmental and clinical trials (Titus et
al. 2016).

To conclude, cognitive impairment is a detrimental symptom
common amongst neurological disease and injury. With the ageing population, the
prevalence and expenditure of such conditions is expected to reach epidemic
proportions, therefore the need for pharmacological agents to tackle the
cognition dysfunction is in extreme demand. Apart from AChE inhibitors and NMDA
antagonists, there is currently limited therapeutic options available. However,
as more is understood about the pathology and molecular mechanism of the brain
through ongoing research, the potential for therapeutic success in treating
cognitive impairment remains hopeful.           

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