As mentioned in our earlier post, there is lot more in store for you in terms of Ketogenic diet (KD) and exercise in neurological conditions. So let us understand how exercise creates a myriad effects.

Last week we explained you one of the most important factors, namely, BDNF. Now let us examine other mechanisms:-

First let us look at the effect of KD on various neurological disorders.(Kristin W. Barañano et al, 2008) and then we will take a look at the symbiotic effect of exercise.

Metabolic defects:

The utility of the ketogenic diet in PDH deficiency and GLUT-1 deficiency likely derives from its ability to provide 2-carbon substrates, with subsequent relief of blocks in metabolism upstream from the tricarboxylic acid cycle.

• Phosphofructokinase (PFK) deficiency: Swoboda KJ (1997) in a study observed that a patient with PFK deficiency displayed marked gains in muscle strength and improvement in his developmental milestones after being placed on the ketogenic diet.
• Glycogenosis type V (McArdle disease), which is caused by a defect in the muscle-specific isozyme of glycogen phosphorylase. Busch V et al (2005) observed that after initiation of ketogenic diet, the patient’s exercise tolerance improved and there was a trend toward decreased baseline creatine kinase levels.

Malignancy: Ketogenic diets (some using calorie restriction) have been associated with decreased tumor growth in animal models of gliomas, prostate cancer, and gastric cancer. Unlike normal cells, cancer cells have both a high glycolytic rate and are dependent on glucose for energy metabolism. (D. Krex et al, 2007).  Ketogenic diet targets the difference between cancer cells and our cells as the former are unable to utilize ketones due to mitochondrial defects. KD causes a reduction in lactic acid which in turn reduces the survival and malignant capacity of cancer cells. (Maurer et al, 2011) In the context of cancer, ketone bodies may provide an alternative substrate for ATP production in malignant cells. (Seyfried TN et al, 2005). There are now several case series documenting this in humans.

Trauma and ischemia: In Prins ML et al (2005) study, animal data suggests a role for the ketogenic diet in protection against trauma and ischemia, as ketones may be a preferred fuel in the injured brain

Neurodegenerative disorders: The ketogenic diet appears to enhance mitochondrial function via a number of potential pathways. Given the important role of mitochondrial dysfunction in many neurodegenerative diseases, it is important to outline potential mechanisms of apparent disease-modifying effects of the ketogenic diet.

Ketones are an alternative fuel for those areas of the brain unable to utilize glucose due to paucity of  glucose transporters (Glut) and regional hyper-insulinemia.

There is also data suggesting that calorie restriction itself is protective. Further, the low carbohydrate content, in the ketogenic diet affects glucose utilisation and factors such as brain-derived neurotrophic factor (one example of a potential indirect effect of the diet). (Maswood N et al, 2004)

Multiple Sclerosis:

In an animal study, it was observed that KD significantly reduced motor disability, CNS inflammation and memory dysfunction in experimental autoimmune encephalomyelitis (EAE) mice. (Hao et al, 2012). Sullivan et al, 2004 observed that KD has anti-inflammatory properties and decreases ROS production by increasing the expression and activity of mitochondrial uncoupling proteins. This could be especially useful in progressive forms of MS.

Parkinson’s disease:

PD is a neurodegenerative condition in which the impairment of mitochondrial complex I activity is hypothesized to play a role in the death of the dopaminergic neurons of the substantia nigra pars compacta. Various investigators have hypothesized that ketones could bypass complex I to provide an alternative fuel source for neurons at risk. Alternatively, ketone bodies may enhance mitochondrial function and thus ATP production, thereby protecting cells against various insults that demand high levels of usable energy (Kashiwaya Y et al, 2000).

Alzheimer disease:

There is glucose hypometabolism and insulin resistance in Alzheimer’s patients. Lowered glucose supply could in turn lead to regional energy deprivation and neuronal damage with consequent further lowering of glucose demand and ultimately leading to cognitive loss. The reduction in glucose uptake and therefore energy deprivation can be remedied by a supply of an alternative energy source like ketones. (Cunnane et al, 2016). The ketogenic diet also may function in a neuroprotective fashion in AD (Kashiwaya Y et al, 2000).

Amyotrophic lateral sclerosis : Recent animal studies suggest a role for the ketogenic diet as a potential therapy for amyotrophic lateral sclerosis (ALS). ALS results from the death of motor neurons in the brain and spinal cord. Zhao Z et al (2006) study suggested that ketosis induced by the ketogenic diet might affect progression of the disease.

Autism : Evangeliou A et al( 2003) observed a variant of the ketogenic diet which were applied to children with autism who showed improved performance and also were appeared to respond better. Ahola-Erkkila et al (2010) study suggested that ketones might improve mitochondrial function by enhancing mitochondrial biogenesis in murine models.

Depression: Murphy P et al (2004) suggested that the ketogenic diet can result in behavioral changes similar to those seen after antidepressants are administered.

Migraine headache, narcolepsy: Few studies reported that dietary therapies similar to the ketogenic diet also may be useful in the treatment of migraine headaches and narcolepsy (Strahlman 2006 ;Husain AM et al, 2004).

Effect of exercise on Neurological disorders

Effect of exercise	Neurological disorders	References
Prevents cognitive decline	Alzheimer’s	Behrman S et al (2014)
Neuroprotective agent	Parkinson’s	Zigmond MJ et al (2014)
Anxiety and stress reduction	In depression	Salmon P (2001)
Improve learning and memory	Autism	Carl W.Cotman et al(2007)
Neurogenesis	Cancer	Mustroph ML et al(2012)
Reduces oxidative stress	Parkinson’s, Alzheimer’s and cancer.	Zsolt RadaÂk et al(2001)
Enhances brain plasticity	Epilepsy, Alzheimer’s	Carl W.Cotman et al (2002)

Now let us examine the mechanism of exercise i.e. how exercise benefits the functioning of our brain by releasing various neurotransmitters which have different role to play in various neurological disorders which is beautifully explained in below diagram and further in detail explained in the book Spark – The Revolutonary New Science ofExercise and the Brain-by Dr. John Ratey.

Mechanism of Exercise:

We would like to conclude that there are perquisites when the positive effects of ketogenic diet in neurological disorders are combined with exercise which also releases endorphins, also known as “feel good” chemicals (neurotransmitters), in your brain.

‘So feel good by exercising while on keto diet’.

References:-

1. Kristin W. Barañano et al. The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses. Curr Treat Options Neurol. 2008 November ; 10(6): 410–419.
2. Swoboda KJ, Specht L, Jones HR, et al. Infantile phosphofructokinase deficiency with arthrogryposis: clinical benefit of a ketogenic diet. J Pediatr 1997;131:932–934.
3. Busch V, Gempel K, Hack A, et al. Treatment of glycogenosis type V with ketogenic diet [letter]. Ann Neurol 2005;58:341.
4. Krex, Dietmar, Barbara Klink, Christian Hartmann, Andreas von Deimling, Torsten Pietsch, Matthias Simon, Michael Sabel et al. Long-term survival with glioblastoma multiforme. Brain130, no. 10 2007; 2596-2606.
5. Maurer GD, Brucker DP, Bahr O, et al. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer. 2011; 26(11):315.
6. Seyfried TN, Mukherjee P. Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (London) 2005;2:30.
7. Prins ML, Fujima LS, Hovda DA. Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J Neurosci Res 2005;82:413–420.
8. Maswood N, Young J, Tilmont E, et al. Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci U S A 2004;101:18171–18176.
9. Hao, Junwei, Ruolan Liu, Gregory Turner, Fu-Dong Shi, and Jong M. Rho. “Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis.” PloS one7, 2012; e35476.
10. Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Annals of neurology. 2004 Apr 1;55(4):576-80.
11. Cunnane, Stephen C., Alexandre Courchesne‐Loyer, Valérie St‐Pierre, Camille Vandenberghe, Tyler Pierotti, Mélanie Fortier, Etienne Croteau, and Christian‐Alexandre Castellano. “Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease.” Annals of the New York Academy of Sciences1367, no. 1 2016: 12-20.
12. Kashiwaya Y, Takeshima T, Mori N, et al. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci U S A 2000;97:5440–5444.
13. Zhao Z, Lange DJ, Voustianiouk A, et al. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci 2006;7:29.
14. Evangeliou A, Vlachonikolis I, Mihaildou H, et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol 2003;18:113–118.
15. Ahola-Erkkila S, Carroll CJ, Peltola-Mjosund K, Tulkki V, Mattila I, Seppanen-Laakso T, et al. Ketogenic diet slows down mitochondrial myopathy progression in mice.Hum Mol Genet 2010 19:1974–8410.
16. Murphy P, Likhodii S, Nylen K, Burnham WM. The anti-depressant properties of the ketogenic diet. Biol Psychiatry 2004;56:981–983.
17. Strahlman RS. Can ketosis help migraine sufferers? A case report. Headache 2006;46:182.
18. Husain AM, Yancy ST, Carwile PP, et al. Diet therapy for narcolepsy. Neurology 2004;62:2300– 2302.
19. 19.  Behrman S et al. Can exercise prevent cognitive decline? Practitioner. 2014 Jan;258(1767):17-21, 2-3.
20. 20.  Zigmond MJ et al. Exercise: is it a neuroprotective and if so, how does it work? Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S123-7

1. Salmon P (2001). Effect of physical exercise on anxiety,depression and sensitivity to stress- A Unifying Theory. Clinical Psychology Review, 21, 33-61.
2. Carl W.Cotman et al. Exercise builds brain health: key roles of growth factor cascades and inflammation.Trends in Neurosciences, Volume 30, Issue 10, October 2007, Pages 489
3.  Mustroph ML et al. Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience. 2012 Sep 6;219:62-71

1. Zsolt RadaÂk et al. Regular exercise improves cognitive function and decreases oxidative damage in rat brain.Neurochemistry International 38 (2001) 17±23
2.  Carl W.Cotman et al. Exercise: a behavioral intervention to enhance brain health and plasticity.Trends in Neurosciences, Volume 25, Issue 6, 1 June 2002, Pages 295-301
3. Spark– The Revolutonary New Science of Exercise and the Brain-by Dr. John Ratey.