117 In another study, cannabis extract did not produce a functionally significant improvement in MS-associated tremor.118 Suppression of acquired pendular nystagmus (involuntary movement of the eyes) was seen in a patient with MS after smoking cannabis resin, but not after taking nabilone tablets or orally administered capsules containing cannabis oil.119 There are also findings suggestive of a clinical effect of cannabis on urge incontinence episodes in patients with MS.120 In the treatment of MS, as well as in pain reduction described Inhibitors,research,lifescience,medical earlier, there is a preferential effect of a THC+CBD combination (Sativex).121

A mixture of 2.5 mg THC and 0.9 mg cannabidiol (CBD) lowered spasm frequency and increased mobility, with tolerable side effects, in MS patients with persistent spasticity Inhibitors,research,lifescience,medical not responding to other drugs.122 Oromucosal sprays of Sativex significantly reduced spasticity scores in comparison with placebo.123 Long-term use of Sativex maintains its effect in those patients who perceive initial benefit.124 Zajicek et al originally reported that cannabinoids did not have a beneficial effect on spasticity; however, there was an objective improvement in mobility and some patients reported an improvement in pain.125 Later the same group also found positive effects

on muscle spasticity with Inhibitors,research,lifescience,medical prolonged treatment.126 The subject has been thoroughly reviewed.99,127,130 MS is not the only disease state where the neuroprotective potential of cannabinoids can be seen.

In animal experiments, 2 weeks after the application of 6-hydroxydopamine, a significant depletion of dopamine contents and Inhibitors,research,lifescience,medical a reduction in tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-messenger ribonucleic acid (mRNA) levels in the substantia nigra. Daily administration of THC over 2 weeks produced a significant irreversible Inhibitors,research,lifescience,medical waning in the magnitude of these changes, which may be relevant in the treatment of Parkinson’s disease Brefeldin_A (see below)131 The cannabinoids have a neuroprotective activity not only in vitro but also in vivo: HU-210, a potent synthetic analog of THC, increases NSC639966 survival of mouse cerebellar granule cells exposed to 6-hydroxydopamine.131 In a model of experimental stroke, rimonabant reduced infarct volume by approximately 40 %. Rimonabant exerted neuroprotection independently of its following website cannabinoid receptor-blocking effect.132 In clinical trials, dexanabinol-treated patients achieved significantly better intracranial pressure/cerebral perfusion pressure control without jeopardizing blood pressure. A trend toward faster and better neurologic outcome was also observed.

9 Virtually all cognitive tasks that require effortful

processing are thought to require working memory. There are a range of models of working memory,10,11 but most are variants of the Baddeley model.9 Regardless of the view one adopts, there is no question that working selleck chem DAPT secretase memory declines with age, particularly the processing or central executive component, as evidenced by the data presented in Figure 1.12,13 Hasher and Zacks14 have emphasized the Inhibitors,research,lifescience,medical role of inhibition, rather than working memory, in age-related cognitive declines. They etc proposed that older adults are less effective at inhibiting irrelevant information than young adults. They argue that working memory capacity is not limited with age, but rather is filled with “mental clutter” so that capacity appears to be diminished. Older adults are assumed to be particularly deficient Inhibitors,research,lifescience,medical in a deletion operation in working memory whereby irrelevant information is efficiently discarded when it is no longer needed. There is considerable evidence that older adults have difficulty inhibiting irrelevant information in working memory.15-18 There is Inhibitors,research,lifescience,medical also evidence that older adults have difficulty in flexibly deploying mental resources and/or switching among different tasks. Two good everyday examples

that require task switching are day-trading stocks and piloting an airplane. Both the day trader and airline pilot must constantly shift attention among various indicators and adjust their behavior accordingly (eg, trade a stock or adjust altitude). There is considerable evidence that older Inhibitors,research,lifescience,medical adults have difficulty

switching from one operation to another relative to young adults,19-21 with older adults showing larger time costs for switching between tasks (or metaphorically, reloading mental software) than young adults, Inhibitors,research,lifescience,medical when compared with receiving repeated trials on the same task. Another process that is important for many cognitive tasks, but particularly long-term memory tasks, is the ability to connect a memory event to a context. For example, an older adult may remember that he was told to take shark cartilage to improve his/her arthritis. What the older adult may not remember is whether they were instructed GSK-3 to do this by a personal physician or were told to do this by a friend who had just read it in the popular press. Thus, the older adult may find they remember a fact, but not the source of the information.22,23 This decreased ability to bind target information to source or context is a problem for older adults in long-term memory tasks24-26 as well as working memory.15 Finally, there is no question that long-term memory declines with age (Figure 1). Problems with decreases in speed, working memory, switching, inhibition, and binding could all contribute to poor long-term memory.