Ladostigil a novel multifunctional drug for the treatment of dementia comorbid with depression

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M. Weinstock1, L. Luques1, C. Bejar1, and S. Shoham2

1 Department of Pharmacology, Hebrew University Hadassah School of Medicine, and 2 Research Department, Herzog Hospital Jerusalem, Israel

Summary. Ladostigil is a novel drug that inhibits acetyl and butyrylcholinesterase, and monoamine oxidase (MAO) A and B selectively in the brain. It reverses memory deficits induced by chronic inhibition of cortical cytochrome oxidase in rats and has anxiolytic and antidepressant-like activity in prenatally-stressed rats. Ladostigil also prevents oxi-dative-nitrative stress induced in astrocytes in the hippocampal CA1 region following icv injection of STZ in rats which also impairs their episodic memory. The unique combination of ChE and MAO enzyme inhibition combined with neuroprotection makes lados-tigil a potentially useful drug for the treatment of dementia in subjects that also have extrapyramidal dysfunction and depression.

Introduction

Progressive neuronal loss resulting in deficits in cortical cholinergic transmission occurs in the three major forms of dementia, Alzheimer (AD) vascular (VD) and dementia with Lewy bodies (DLB). These deficits are strongly correlated with impairment of attention and cognitive function (Ellis, 2005). A significant proportion of patients with each of these forms of dementia have extrapyramidal dysfunction and depression. Although the aetiology of these dementias is not known, the oxidation of cell constituents, membrane lipids and DNA are seen in the ageing brain resulting from overproduction of oxidative free radicals (ROS) because of its diminished capacity to remove them. ROS could either be the cause or the result of the mitochon-drial dysfunction in AD indicated by the reduction in cytochrome oxidase (COx) activity in several cortical and hippocampal brain regions (Hirai et al., 2001). Impaired mitochondrial activity together with reduced levels of ATP can lead to apoptosis and cell death. ROS may also be the cause of activation of glial cells with increased regional expression of cytokines and nitric oxide (NO) in the brains of patients with dementia that both results from and contributes to the production of b-amyloid and neurodegeneration (Katsuse et al., 2003).

Pharmacological rationale

To date, acetylcholinesterase (AChE) inhibitors are the only drugs that have been shown to produce significant symptomatic improvement in cognitive performance and behavioural abnormalities in subjects with AD, VD and DLB (Bullock, 2004). While AChE inhibitors slow the decline in cognitive impairment and executive function, there is no evidence that they can reduce oxidative stress in vivo or ameliorate depression. Ladostigil, (TV3326) was designed to increase choliner-

gic transmission, prevent the formation of ROS or their actions and ameliorate depression. It is an aminoindan containing the pro-pargylamine group found in the selective, monoamine oxidase (MAO)-B inhibitor rasa-giline and the carbamate moiety of rivastig-mine. Ladostigil inhibits both AChE and butyrylcholinesterase (BuChE) and has a longer duration of action than rivastigmine. In contrast to other irreversible MAO-A inhibitors ladostigil has very little or no effect on the enzyme in the gastro-intestinal tract at doses that block MAO-A and B in the brain by more than 80%. It therefore causes minimal potentiation of the cardiovascular effect of orally-administered tyramine. This selective inhibition probably results from the formation in the brain of the decarbamylated metabolite which is a much more potent inhibitor of MAO than ladostigil itself (Weinstock et al., 2003).

Antagonism of memory induced in rats by inhibition of brain cytochrome oxidase

In order to mimic the reduction in COx activity seen in the cortex and hippocampus of AD patients we administered sodium azide (NaAz) (1 mg/kg/hour) for 4 weeks to male rats via Alzet minipumps. This resulted in a selective decrease of 20-25% in enzyme activity in the cingulate and parietal cortices and in the dentate gyrus and CA1 region of the hippocampus. The rats showed a loss of episodic memory in the object recognition test that was restored by a single oral dose of ladostigil (50 mmol/kg) administered two hours before the test (Table 1). This dose inhibits AChE in the frontal cortex by 39 ± 3% which agrees well with the values of inhibition obtained with both rivastigmine and donepezil in patients with AD (Kaasinen et al., 2002). When administered chronically to rats for 4 weeks from one day after instillation of the NaAz pump, ladostigil (50 mmol/kg) prevented the deficit in working memory in the Morris water maze test even when the rats were tested 20-22 hours after its administration when brain AChE was no longer inhibited. These findings suggest that ladostigil can reverse existing memory impairment and may also be able to prevent its development if given early enough.

Anxiolytic and antidepressant-like activity of ladostigil

Antidepressants are at least as effective as benzodiazepines in the treatment of generalized anxiety disorder that may precede or accompany depressive symptoms. Anxiolytic behaviour with features of depression can be

Table 1. Reversal by ladostigil of deficit in episodic memory induced in rats by chronic inhibition of cerebral cytochrome oxidase

Table 1. Reversal by ladostigil of deficit in episodic memory induced in rats by chronic inhibition of cerebral cytochrome oxidase

Treatment

Trial 1: Two identical objects Total exploration time (sec) ± sem

Trial 2: One familiar and one new object

Total exploration time (sec) ± sem

Diff new-familiar (sec) ± sem

Discrimination^ index ± sem

Sham pump (10)

17.4 ± 1.7

21.3 ± 3.2

7.7 ± 1.9*

0.32 ± 0.06*

NaAz (10)

29.8 ± 6.2

24.3 ± 3.9

-3.1 ± 3.2

-0.05 ± 0.12

NaAz + ladostigil

20.4 ± 2.5

25.8 ± 2.9

8.7 ± 1.3*

0.36 ± 0.07*

50 mmol/kg (10)

(Number of rats) ^Discrimination index: Time exploring new object-time exploring familiar object/total exploration time. * Significantly different from 0 (i.e. show discrimination or spend more time exploring new object)

(Number of rats) ^Discrimination index: Time exploring new object-time exploring familiar object/total exploration time. * Significantly different from 0 (i.e. show discrimination or spend more time exploring new object)

induced in rats by prenatal stress (Weinstock, 2001). These can be detected in the elevated plus maze (EPM) test by an avoidance of the open arms, and in the forced swim test (FST) by a lomger duration of immobility than in control rats. Ladostigil (50 mmol/kg) administered daily for 6 weeks from puberty to prenatally-stressed rats abolished their hyper-anxiety and depressive-like behaviour in the EPM and FST tests in adulthood. This dose inhibited brain MAO-A and B by 60-65% but had no effect on the behaviour of control rats. In human subjects, amelioration of symptoms by antidepressant treatment is usually accompanied by restoration to normal of the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Prenatal stress in rats also disrupts the regulation of the response of the HPA axis to stress, as seen in the delay in return to normal of plasma corticosterone. Chronic treatment with ladostigil normalized the response of the HPA axis in these rats (Poltyrev et al., 2005).

Reduction of oxidative-nitrative stress in vivo by ladostigil

Ladostigil, (0.1-1 mM) prevents cytotoxicity in cell culture induced by the NO donor, Sin 1 or 6 hydroxydopamine in SHSY5Y and PC12

cells. The cytoprotective activity of ladostigil is due to the presence of the propargylamine moiety and occurs at concentrations that are too low to inhibit either AChE or MAO (Youdim and Weinstock, 2002). We have found that intracerebroventricular injection of streptozotocin (icv-STZ) in rats causes deficits in spatial memory 4-6 weeks later that result from pathological processes in the septo-hippocampal system that include selective damage to myelin. The memory deficits are significantly reduced by chronic treatment with ladostigil (Weinstock and Shoham, 2004). We now report that icv STZ causes activation of astrocytes, as indicated by GFAP staining, one week after its injection before memory deficits are seen. These active astrocytes display oxidative-nitrative stress (indicated by a specific antibody to nitrotyrosine) in the alveus, stratum oriens and stratum radiatum in the hippocampus. Ladostigil (2.9 mmol/kg) given once daily for one week before, until one week after icv STZ virtually abolished the astrocyte activation and nitrotyrosine staining (Fig. 1). This dose does not inhibit AChE or MAO in the brain but is compatible with that of other propargylamino-indan compounds that reduce oxidative stress in cell culture (Youdim and Weinstock, 2002).

Alveus S-Oriens S-Radiatum

Hippocampal areas

Fig. 1. Prevention by ladostigil of oxidative-nitrative stress in astrocytes in hippocampal CA1 regions induced in rats by icv STZ. *Significantly different from other groups, P < 0

Alveus S-Oriens S-Radiatum

Hippocampal areas

Fig. 1. Prevention by ladostigil of oxidative-nitrative stress in astrocytes in hippocampal CA1 regions induced in rats by icv STZ. *Significantly different from other groups, P < 0

446 M. Weinstock et al.: Ladostigil, a novel drug for the treatment of dementia co-morbid with depression

Conclusions

Ladostigil is a multifunctional drug designed to answer the therapeutic requirements of progressive neurodegenerative diseases with features of dementia, depression and extrapyramidal symptoms. It inhibits AChE and BuChE and has a slower onset and longer duration of action than rivastigmine. Lados-tigil antagonizes memory deficits induced by scopolamine, icv STZ or chronic COx inhibition in rats, closed head injury in mice or advanced age in monkeys (Buccafusco et al., 2003). It may therefore be expected to provide similar beneficial effects on cognitive function and attention in patients with AD, VD and DLB to those seen by AChE inhibitors currently in use.

In addition, the unique ability of ladosti-gil to inhibit both MAO-A and B selectively in the brain enables the drug to exert anxio-lytic and antidepressant-like activity without causing clinically significant potentiation of the pressor response to oral tyramine. MAO inhibition by ladostigil prevented the decline in striatal dopamine induced by the neuro-toxin MPTP in mice and should also help to maintain dopamine levels in subjects with Parkinson's disease and dementia. Since oxi-dative stress and gliosis occur in neurode-generative disorders like AD, the ability of ladostigil to reduce these features in a rat model in vivo suggests that it may also be able to reduce neurodegeneration and slow disease development. These multiple pharmacological actions of ladostigil make it a potentially useful drug for the treatment of dementia with extrapyramidal dysfunction and depression.

Acknowledgement

The authors gratefully acknowledge the financial support of Teva Pharmaceuticals Ltd.

References

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Hirai K, Aliev G, Nunomura A, et al. (2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 21: 3017-3302 Kaasinen V, Nagren K, Jarvenpaa T, et al. (2002) Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease. J Clin Psychopharmacol 22: 615-620 Katsuse O, Iseki E, Kosaka K (2003) Immunohisto-chemical study of the expression of cytokines and nitric oxide synthase in brains of patients with dementia with Lewy bodies. Neuropathology 23: 9-15 Poltyrev T, Gorodetsky E, Bejar C, et al. (2005) Effect of chronic treatment with ladostigil (TV-3326), on anxiogenic and depressive-like behaviour and on activity of the hypothalamic pituitary adrenal axis in male and female prenatally-stressed rats. Psy-chopharmacology 181: 118-125 Weinstock M (2001) Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 65: 427-451 Weinstock M, Gorodetsky E, Poltyrev T, et al. (2003) A novel cholinesterase and brain-selective mono-amine oxidase inhibitor for the treatment of dementia co-morbid with depression and Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry 27: 555-561 Weinstock M, Shoham S (2004) Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm 111: 347-366 Youdim MBH, Weinstock M (2001) Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug, TV3326 [(N-propargyl-(3R) aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol 21: 555-573

Author's address: Prof. M. Weinstock, Department of Pharmacology, Hebrew University Hadassah School of Medicine, Ein Kerem, Jerusalem 91120, Israel, e-mail: [email protected]

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